Small molecule activators of nicotinamide phosphoribosyltransferase (nampt) and uses thereof

ABSTRACT

Provided herein are small molecule activators of Nicotinamide Phosphoribosyltransferase (NAMPT), compositions comprising the compounds, and methods of using the compounds and compositions.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Patent ApplicationNo. 62/444,557 filed on Jan. 10, 2017, incorporated herein by referencein its entirety.

FIELD OF THE INVENTION

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting stepin the nicotinamide (NAM) salvage pathway which culminates in NAD⁺biosynthesis. NAMPT synthesizes nicotinamide mononucleotide (NMN) andpyrophosphate from NAM and α-D-5-phosphoribosyl-1-pyrophosphate. NAMPTalso catalyzes ATP hydrolysis which promotes NMN production via aphosphoenzyme intermediate (His247). Described are small moleculeactivators of NAMPT and uses of such activators in the treatment ofdiseases or conditions that would benefit by NAMPT activation.

SUMMARY OF THE INVENTION

Described herein are compounds that are nicotinamidephosphoribosyltransferase (NAMPT) modulators, and compositions, andmethods of using these compounds and compositions.

In one aspect, described herein is a compound that has the structure ofFormula (I), or a pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein:    -   each R¹ is independently selected from the group consisting of        H, D, C₁-C₄alkyl and C₁-C₄deuteroalkyl;    -   R² is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   R³ is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   or R² and R³ are taken together with the intervening atoms        joining R² and R³ to form a 5- or 6-membered ring;    -   ring A is a monocyclic ring that is a 6-membered heteroaryl, a        5-membered heteroaryl, or phenyl;    -   each R^(a) is independently selected from the group consisting        of H, D, halogen, —CN, —OH, —N(R⁶)₂, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted monocyclic        carbocycle, and substituted or unsubstituted monocyclic        heterocycle;    -   R⁶ is H, D, or substituted or unsubstituted C₁-C₆alkyl;    -   n is 0, 1, 2, 3, or 4;    -   each R⁴ is independently selected from the group consisting of        H, D, halogen, —CN, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, and substituted or        unsubstituted C₁-C₆heteroalkyl;    -   m is 0, 1, 2, 3, or 4;    -   X is absent, —X¹-L¹- or L¹-X¹;    -   X¹ is selected from the group consisting of —O—, —S—, —SO₂—,        —NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —C(═O)—, —OC(═O)NR⁵—, —NR⁵C(═O)O—, and        —NRC(═O)NR⁵—;    -   each R⁵ is independently selected from the group consisting of        H, D, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        and substituted or unsubstituted benzyl;    -   L¹ is absent or substituted or unsubstituted C₁-C₄alkylene;    -   Y is selected from the group consisting of H, D, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted benzyl,        substituted or unsubstituted naphthyl, and substituted or        unsubstituted heteroaryl, wherein if Y is substituted then Y is        substituted with 1-4 R⁷ groups;    -   each R⁷ is independently selected from the group consisting of        D, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹,        —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹,        —NH₂, —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹,        —NR⁸C(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NRC(═O)OR⁹, a        substituted or unsubstituted C₃-C₆cycloalkyl, a substituted or        unsubstituted C₂-C₆heterocycloalkyl, a substituted or        unsubstituted aryl, and a substituted or unsubstituted        heteroaryl;    -   each R⁸ is independently selected from the group consisting of        H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, and C₁-C₆heteroalkyl;    -   each R⁹ is independently selected from the group consisting of        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₆cycloalkyl, a substituted or unsubstituted        C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, a substituted or        unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a        substituted or unsubstituted —C₁-C₄alkylene-aryl, and a        substituted or unsubstituted —C₁-C₄alkylene-heteroaryl;    -   or when R⁸ and R⁹ are attached to the same N atom then R⁸ and R⁹        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle;    -   or when Y and R⁵ are attached to the same N atom then Y and R⁵        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

In some embodiments, the compound of Formula (I) has the structure ofFormula (III), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (I) has the structure ofFormula (IV), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

In some embodiments, the compound of Formula (IV) has the structure ofFormula (V), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

In some embodiments, compound of Formula (I), or a pharmaceuticallyacceptable salt, or solvate thereof has the structure of Formula (Ia),or a pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein:

-   -   X is absent or -L¹-X¹-L²-;        -   L¹ is absent or —CH₂—        -   X¹ is selected from the group consisting of —O—, —S—, —SO₂—,            —NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—,            —C(═O)O—, —OC(═O)O—, —C(═O)—, —OC(═O)NR⁵—, —NR⁵C(═O)O—, and            —NR⁵C(═O)NR⁵—;            -   each R⁵ is independently selected from the group                consisting of H, D, substituted or unsubstituted                C₁-C₆alkyl, substituted or unsubstituted                C₁-C₆deuteroalkyl, substituted or unsubstituted                C₁-C₆fluoroalkyl, substituted or unsubstituted                C₃-C₆cycloalkyl, and substituted or unsubstituted                benzyl;        -   L² is absent or substituted or unsubstituted C₁-C₄alkylene;    -   Y is selected from the group consisting of H, D, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted benzyl,        substituted or unsubstituted naphthyl, and substituted or        unsubstituted heteroaryl, wherein if Y is substituted then Y is        substituted with 1-4 R⁷ groups;        -   each R⁷ is independently selected from the group consisting            of D, —CN, F, Cl, Br, I, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,            —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹, —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹, —NH₂, —NR⁸R⁹,            —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹,            —NRC(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,            substituted or unsubstituted C₁-C₆alkyl, substituted or            unsubstituted C₁-C₆deuteroalkyl, substituted or            unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstituted            C₁-C₆heteroalkyl, a substituted or unsubstituted            C₃-C₆cycloalkyl, a substituted or unsubstituted            C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl,            or a substituted or unsubstituted heteroaryl, a substituted            or unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a            substituted or unsubstituted            —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a substituted or            unsubstituted —C₁-C₄alkylene-aryl, and a substituted or            unsubstituted —C₁-C₄alkylene-heteroaryl;            -   each R⁸ is independently selected from the group                consisting of H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, and                C₁-C₆heteroalkyl;            -   each R⁹ is independently selected from the group                consisting of C₁-C₆alkyl, C₁-C₆fluoroalkyl,                C₁-C₆heteroalkyl, a substituted or unsubstituted                C₃-C₆cycloalkyl, a substituted or unsubstituted                C₂-C₆heterocycloalkyl, a substituted or unsubstituted                aryl, a substituted or unsubstituted heteroaryl, a                substituted or unsubstituted                —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted or                unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a                substituted or unsubstituted —C₁-C₄alkylene-aryl, and a                substituted or unsubstituted —C₁-C₄alkylene-heteroaryl;            -   or when R⁸ and R⁹ are attached to the same N atom then R                and R⁹ are taken together with the N atom to which they                are attached to form a substituted or unsubstituted                C₂-C₁₀heterocycle;        -   or when Y and R⁵ are attached to the same N atom then Y and            R⁵ are taken together with the N atom to which they are            attached to form a substituted or unsubstituted            C₂-C₁₀heterocycle;        -   provided that when ring A is pyridin4-yl then —X—Y is not            —SO₂NHbenzyl, —SO₂NH(4-tert-butylphenyl) or            —NHSO₂(2,5-ditrifluoromethylphenyl).

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (IIa), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (IIIa), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (IVa), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (Va), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa),(IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof,and at least one pharmaceutically acceptable excipient.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceuticallyacceptable salt thereof, is formulated for administration to a mammal byintravenous administration, subcutaneous administration, oraladministration, inhalation, nasal administration, dermal administration,or ophthalmic administration. In some embodiments, the compound ofFormula (I), (Ia), (II), (Ia), (III), (IIIa), (IV), (IVa), (V) or (Va),or a pharmaceutically acceptable salt thereof, is in the form of atablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion,a solution, an emulsion, an ointment, or a lotion.

In one aspect, described herein is a method of treating a disease orcondition mediated by nicotinamide phosphoribosyltransferase (NAMPT)activity in a mammal comprising administering a NAMPT activator compoundas described herein, or a pharmaceutically acceptable salt, solvate,prodrug, or N-oxide thereof, to the mammal.

In some embodiments, the disease or condition is cancer.

In some embodiments, the disease or condition is hyperproliferativedisease or condition.

In some embodiments, the disease or condition is an inflammatory diseaseor condition.

In some embodiments, the disease or condition is a metabolic disorder.

In some embodiments, the disease or condition is a neurodegenerativedisorder.

In some embodiments, the disease or condition is a muscle wastingdisorder.

In some embodiments, the disease or condition is a neurodegenerativedisease.

In another aspect, described herein is the use of a NAMPT activatorcompound as described herein, or a pharmaceutically acceptable salt,solvate, prodrug, or N-oxide thereof, in the manufacture of a medicamentfor the treatment or prevention of a disease or condition that ismediated by NAMPT activity.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the NAMPT activator compound, issystemically administered to the mammal; and/or (b) the effective amountof the NAMPT activator compound is administered orally to the mammal;and/or (c) the effective amount of the compound of the NAMPT activatorcompound is intravenously administered to the mammal; and/or (d) theeffective amount of the NAMPT activator compound is administered byinhalation; and/or (e) the effective amount of the NAMPT activatorcompound is administered by nasal administration; or and/or (f) theeffective amount of the NAMPT activator compound is administered byinjection to the mammal; and/or (g) the effective amount of the NAMPTactivator compound is administered topically to the mammal; and/or (h)the effective amount of the NAMPT activator compound is administered byophthalmic administration; and/or (i) the effective amount of the NAMPTactivator compound is administered rectally to the mammal; and/or (j)the effective amount is administered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the NAMPT activatorcompound, including further embodiments in which (i) the compound isadministered once; (ii) the compound is administered to the mammalmultiple times over the span of one day; (iii) continually; or (iv)continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the NAMPT activatorcompound, including further embodiments in which (i) the compound isadministered continuously or intermittently: as in a single dose; (ii)the time between multiple administrations is every 6 hours; (iii) thecompound is administered to the mammal every 8 hours; (iv) the compoundis administered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In any of the aforementioned aspects involving the administration of acompound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va), or a pharmaceutically acceptable salt thereof, to a subjectare further embodiments comprising administering at least one additionalagent in addition to the administration of a NAMPT activator compound,or a pharmaceutically acceptable salt thereof. In various embodiments,the NAMPT activator compound and the additional agent are administeredin any order, including simultaneously. In some embodiments, the NAMPTactivator compound and the additional agent are administered to thesubject in the same pharmaceutical composition or in separatepharmaceutical compositions.

In any of the embodiments disclosed herein, the subject is a human.

In some embodiments, compounds and compositions provided herein areadministered to a human.

In some embodiments, compounds and compositions provided herein areorally administered.

Articles of manufacture, which include packaging material, a NAMPTactivator compound, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, tautomers, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or solvate thereof, is used for the treatment of diseases or conditionsthat would benefit from the activation of NAMPT, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Nicotinamide phosphoribosyltransferase (NAMPT) is an essentialintracellular enzyme involved in mammalian biosynthetic pathway ofnicotinamide adenine dinucleotide (NAD), a coenzyme participating inadenosine triphosphate (ATP) production and redox metabolism. Thepathway includes the first rate-limiting step of the NAMPT-catalyzedsynthesis of nicotinamide mononucleotide from nicotinamide, and thesecond step which is a subsequent conversion of nicotinamidemononucleotide to NAD catalyzed by nicotinamide mononucleotideadenyltransferase (NMNAT). It was established that rapid NAD depletionin brain tissue inevitably suppresses ATP generation, which in turndisrupts intracellular energy homeostasis and eventually leads to thecell death and to the brain injuries. Upregulation of NAMPT has beenshown as a response to the decreased NAD level in several ischemicstroke models, including several clinical studies.

In addition to its role in intracellular energy production, NAMPT alsoplays a critical role in sirtuin (SIRT) signaling, which is a keyendogenous defense element against various stresses, cell metabolichomeostasis, survival, and aging. NAMPT expression and activity can beregulated by various stimuli, including circadian rhythms, diet, caloricintake restriction, stress, aging, and disease.

Based on importance of NAMPT in regulation of NAD and ATP levels, thecompounds which alter NAMPT expression and activity are considered to beuseful in treating or preventing the brain injuries which areaccompanied by the decreased levels of NAD, including ischemic stroke,hemorrhagic stroke, and traumatic brain injuries. Recently, P7C3chemicals were found to work as activators of NAMPT in cells and theirprolonged administration prevented newborn neuron death and enhancedneurogenesis and preserved cognitive function in aged rodents. Inaddition to their efficacy in animal models of Alzheimer's disease,P7C3s were found to be effective in other models of neurological diseaseincluding Parkinson's disease, amyotrophic lateral sclerosis, traumaticbrain injuries, depression, Down syndrome, and neonatal nerve injury.

Brain Injuries

Stroke is among the most common causes of death and the leading cause ofdisability with high morbidity worldwide. The number of people withfirst stroke is approximately 17 million per year; almost one-third dieand one-third are left permanently disabled. Throughout the world,stroke is responsible for approximately one-tenth of deaths, 33 millionpeople are living with the effects of stroke, and the prevalence ofstroke is rising. Stroke refers to an acute cerebrovascular disorderthat is manifested by sudden loss or deterioration of brain function dueto the disruption in blood supply to the brain. Approximately 78% ofstrokes are ischemic stroke and others are hemorrhagic stroke. Tissueplasminogen activator (tPA) is the only pharmacological therapy approvedfor ischemic stroke, and no drug is available for hemorrhagic stroke.Only a small fraction (3-5%) of stroke patients receives tPA treatment.Therefore, there is an urgent need for developing new drugs to treatstroke. Elucidation of the endogenous defense mechanisms againstcellular injury is considered key to the development of novel stroketherapies. Furthermore, in addition to salvaging the stroke patients atthe acute period, there is the need to provide a solution for strokerehabilitation during the chronic period. Therefore, an ideal target forstroke treatment could be a multifunctional protein with protectionlocally and systemically during acute and chronic phases of stroke.

In the animal ischemic stroke model, upregulation of both intracellularNAMPT and extracellular NAMPT has been observed. In humans, severalclinical studies provided evidence for the elevation of blood NAMPTlevel as a response to the decreased NAD level in different ischemicstroke models. In all studies, NAMPT is described to strongly suppressischemia-induced neuronal death, to inhibit the activation ofmitochondrial apoptotic signaling pathways (such as Bax and Caspase-3),and to reduce mitochondrial membrane potential depolarization. It wasestablished that rapid NAD depletion in brain tissue inevitablysuppresses ATP generation, which in turn disrupts intracellular energyhomeostasis and eventually leads to the cell death and to the braininjuries. Based on importance of NAMPT in regulation of NAD and ATPlevels, the compounds which alter NAMPT expression and activity can beused in treating or preventing brain injuries which are accompanied bythe decreased levels of NAD, including ischemic stroke, hemorrhagicstroke, and traumatic brain injuries.

Metabolic Disorders

NAMPT has been identified as adipocytokine. It was demonstrated thatthis protein is expressed in adipocytes and secreted from adiposetissue, in particular from visceral fat. Adipocytokines mediatebeneficial and detrimental effects in immunity and inflammation. Many ofadipocytokines have a physiological role in metabolism. The uncontrolledsecretions of several adipocytokines were associated with thestimulation of inflammatory processes leading to metabolic disordersincluding obesity, atherosclerosis, insulin resistance, type 2 diabetes,and cardiovascular diseases. Obesity leads to the dysfunction ofadipocytes and correlates with the imbalance of adipocytokines levels.Functional balance of both adipocytes and immune cells is important toexert their effects on metabolic disorders. The loss of NAMPT activitywas linked to type II diabetes in mice. Several clinical studies showedincreased serum NAMPT levels in patients with different metabolicdisorders including obese patients and patients with type 2 diabetes.These studies suggest that potential therapies altering NAMPT levels maybe translated into the future clinical treatments of chronic endocrinemetabolic and inflammatory disorders.

Diabetes mellitus, simply referred to as diabetes, is a syndrome ofdisordered metabolism with hyperglycemia as a hallmark phenotype. It isusually divided into Type 1 and Type 2 diabetes. Type 1 diabetes ischaracterized by loss of the insulin producing p cells of the islets ofLangerhans in the pancreas, leading to a deficiency of insulin. Type 2diabetes is characterized differently due to insulin resistance orreduced insulin sensitivity, combined with a reduced insulin secretion.Diabetes is a complex disease.

In some embodiments, NAMPT activation provides improved Glucosetolerance (GTT) along with insulin secretion and sensitivity. Thepancreas (0-cell, and islets) which releases insulin responds byimproved secretion and response to glucose. In some embodiments, theindices of diabetes are significantly improved with use of NAMPTactivators, both short and long term use.

Another major problem with diabetics is cardiac injury with high risk ofmorbidity and mortality. Major risk factors include myocardial ischemia,diabetic arrhythmogenesis and cardiomyopathy. Co-morbidities includehigher atrial fibrillation, ventricular defects, myocardial damage, andscar formation, which can be attenuated by Nampt activator. In someembodiments, NAMPT activators provide for cardioprotection(anti-ischemic) in a mammal with diabetes.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme in allcells and involved cellular metabolism. Nicotinamidephosphoribosyl-transferase (Nampt) is a regulator of intracellular NAD+.Nampt is able to modulate processes involved in diabetes associatedcardiovascular disease through modulation of NAD+. In some embodiments,NAD+ levels decrease in diabetic mammals and the use of a Namptactivator incrases NAD levels and rescues diabetes. In some embodiments,Nampt activation modulates pyridine nucleotides, altering insulinresistance and insulin release offers cardioprotection.

In some embodiments, a NAMPT activator is used to improve insulinresistance, increases insulin release, insulin secretion, cardiacfunction, or muscle activity, or a combination thereof, in a mammal withdiabetes.

Provided herein are methods for treating metabolic disorders with aNAMPT activator. The NAMPT activator can treat, delay or prevent theonset of a metabolic disorder, wherein such metabolic disorders include,but are not limited to, metabolic syndrome, elevated blood glucoselevels, insulin resistance, glucose intolerance, type 2 diabetes, type 1diabetes, pre-diabetes, non-alcoholic fatty liver disease, nonalcoholicsteatohepatitis, and obesity.

Insulin resistance may be detected using a procedure known as thehyperinsulinemic euglycemic clamp, which measures the amount of glucosenecessary to compensate for an increased insulin level without causinghypoglycemia. In some embodiments, the methods disclosed herein compriseadministering a NAMPT activator to a subject with insulin resistance. Insome embodiments, the NAMPT activator improves insulin sensitivity. Insome embodiments, the NAMPT activator treats a metabolic disorder. Insome embodiments, the NAMPT activator treats a metabolic disorder byimproving insulin sensitivity. In some embodiments, the NAMPT activatordelays or prevents the onset of the metabolic disorder by improvinginsulin sensitivity.

In some embodiments, described herein is a method of improving glucosetolerance in an individual comprising administering a NAMPT activator tothe subject with impaired glucose tolerance. In some embodiments, theindividual has a metabolic disorder and the metabolic disorder istreated by improving glucose tolerance. In some embodiments, the NAMPTactivator delays or prevents the onset of a metabolic disorder in anindividual by improving glucose tolerance.

In some embodiments, described herein is a method of treatment of ametabolic disorder in a subject that is overweight or obese. In someembodiments, a NAMPT activator is used to treat obesity in a subject. Insome embodiments, the NAMPT activator decreases adipose tissue expansionin the subject that is overweight or obese. In some embodiments, themetabolic disorder is treated by decreasing adipose tissue expansion.

In some embodiments, administration of a NAMPT activator to a subjectdelays or prevents the onset of a metabolic disorder by decreasingadipose tissue expansion. In some embodiments, the subject is at riskfor developing a metabolic disorder.

In some embodiments, administration of a NAMPT activator to a subjecttreats, prevents, or ameliorates the symptoms of drug inducedhyperglycemia. In some embodiments, administration of a NAMPT activatorto a subject treats, prevents, or ameliorates the symptoms of druginduced hyperglycemia by reducing blood glucose levels. Pharmacologicalagents can affect glucose homestasis that can result in hyperglycemia.In some embodiments, the hyperglycemia occurs in the absence of adiagnosis of diabetes. If left untreated, the elevated blood glucoselevels can lead to a medical emergency. Symptoms include, but are notlimited to fatigue, weakness, fruity odor of the breath, confusion, lackof concentration, shortness of breath, nausea, vomiting, dry skin, andflushing of the skin. Common drug categories that are associated withcontributing to hyperglycemia include, but are not limited to:antibiotics, such as fluoroquinolones including gatifloxacin;beta-blockers, such as propranolol, metoprolol or atenolol; thiazide,such as hydrochlorothiazide, and thiazide-like diuretics, andthiazide-like drugs (metolazone); second-generation antipsychotics(SGAs) or “atypical antipsychotics” such as olanzapine or clozapine;corticosteroids; calcinuerin inhibitors such as cyclosporine, sirolimusor tarcrolimus; protease inhibitors such as ritonavir.

In some embodiments, administration of a NAMPT activator to a subjecttreats or prevents or delays the onset of stress induced hyperglycemia.In some embodiments, administration of a NAMPT activator to a subjecttreats or prevents or delays the onset of stress induced hyperglycemiaby reducing blood glucose levels. Stressed induced hyperglycemia (SIH)is a transient increase in plasma glucose levels higher than 200 mg/dLwhich occurs during an acute illness or injury. In some embodiments, thehyperglycemia occurs in the absence of a diagnosis of diabetes. The SIHresults from an excess of glucose production relative glucose clearance.SIH has been associated with conditions including, but not limited to,myocardial infarction, stroke, and trauma. SIH has been associated withincrease mortality and a higher incidence of congestive heart failureand cardiogenic shock in patients after myocardial infarction. Strokevictims have higher mortality associated with SIH and worse odds ofdesirable neurological outcomes as glucose levels increase with SIH.Hyperglycemia was also shown to be a predictor of infectiouscomplications in the form of pneumonia, urinary tract infections, woundinfections and bacteria. Overall, published studies have consistentlyshown higher morbidity and higher mortality rates in those patients thatpresent with SIH.

In certain embodiments, the methods provided herein comprise measuringblood glucose levels. Blood glucose levels may be measured before and/orafter administration of a NAMPT activator. Blood glucose levels may bemeasured in whole blood, or may be measured in plasma. Blood glucoselevels may be measured in a clinical laboratory, or may be measuredusing a blood glucose meter.

In certain embodiments, blood glucose levels are measured in a subjectwhen the subject has fasted for at least 8 hours. In certainembodiments, blood glucose levels are measured at random times, and themeasurement is not timed according to the intake of food or drink. Incertain embodiments, blood glucose levels are measured in thepost-prandial state, i.e. after the subject has eaten a meal. In certainembodiments, blood glucose levels are measured in a subject two hoursafter the subject has eaten a meal. In certain embodiments, bloodglucose levels are measured at timed intervals following administrationof glucose to the subject, in order to determine how quickly thesubject's body clears glucose from the blood. Any measurements of bloodglucose levels may be made in whole blood or in plasma.

In certain embodiments, the subject has elevated blood glucose levels.In certain embodiments, a subject is identified as having elevated bloodglucose levels. In certain embodiments, an elevated blood glucose levelis a fasting blood glucose level between 100 and 125 mg/dL. In certainembodiments, an elevated blood glucose level is a fasting blood glucoselevel above 126 mg/dL. In certain embodiments, an elevated blood glucoselevel is a two-hour post-prandial glucose level between 140 and 199mg/dL. In certain embodiments, an elevated blood glucose level is atwo-hour post-prandial glucose level at 200 mg/dL or higher.

In certain embodiments, a subject having elevated blood glucose levelshas pre-diabetes. In certain embodiments, a subject is identified ashaving pre-diabetes. In certain embodiments, a subject having elevatedblood glucose levels has diabetes. In certain embodiments, a subject isidentified as having diabetes according to the subject's blood glucoselevels. In certain embodiments, the methods provided herein comprisemonitoring blood glucose levels before administration of a NAMPTactivator. In certain embodiments, the methods provided herein comprisemeasuring blood glucose levels after administration of a NAMPTactivator. In certain embodiments, a subject measures blood glucoselevels one or more times daily.

In certain embodiments, methods for reducing blood glucose levelscomprise reducing a subject's blood glucose levels to blood glucoselevels determined as desirable by medical organizations, such as theAmerican Diabetes Association or the World Health Organization. Incertain embodiments, blood glucose levels are reduced below 130 mg/dLwhen measured before a subject has had a meal. In certain embodiments,blood glucose levels are reduced to below 180 mg/dL when measured aftera subject has had a meal.

Provided herein are methods for improving insulin sensitivity in asubject comprising administering to the subject a NAMPT activator; andthereby improving insulin sensitivity in the subject. In certainembodiments, the subject has insulin resistance. In some embodiments,the individual with insulin resistance has fasting insulin levels of atleast 20 U/mL. In some embodiments, the individual with insulinresistance has fasting insulin levels that exceed 100 U/mL.

Muscle Wasting Disorder

Aging is the accumulation of changes in an organism over time. Aging isa complex process, depending on both genetic compositions andenvironmental conditions.

Aging is associated with mitochondrial dysfunction due to a specificloss of mitochondrial encoded oxidative phosphorylation subunitsthroughout the life. Mitochondria are responsible for the generation ofcellular energy, in particular NAD and ATP. During aging NAD levels inmitochondria decline which lead to reduction in energy production andreduction of muscle function. As a result, mitochondrial dysfunctionleads to muscle wasting disorders. Deleting SIRT1 and NAMPT acceleratesdecline in nuclear NAD and the accumulation of HIF-1α under normoxicconditions, with parallels to Warburg reprogramming, whereas raising NADlevels in old mice restores mitochondrial function to that of a youngmouse in a SIRT1- and NAMPT-dependent manner. The pseudohypoxic statedisrupts nuclear-mitochondrial communication contributes to the declinein mitochondrial function with age and leads to subsequent muscledisorders, including skeletal and heart muscle disorders. Specificdeletion of NAMPT in adult mice elucidated a critical threshold of NADrequired to maintain the exercise performance, as well as the mass andstrength of muscle, by directly supporting aerobic ATP synthesis.Importantly, these parameters can be rapidly and uniformly restored byadministration of the NAD precursor, nicotinamide riboside. NAMPTactivators aiming to increase intracellular NAD levels will potentiallyreverse the process of muscle wasting disorder.

Axonal degeneration occurs in many neurodegenerative diseases. In someembodiments, NAMPT delays axon degeneration in the presence ofnicotinamide. The increased activity of the NAD biosynthetic pathwaystemming from nicotinamide promotes axonal protection. Exogenousapplication of the NAD precursors can also delay axonal degeneration. Insome embodiments, stimulation of NAD biosynthetic pathways includingNAMPT are useful in preventing or delaying axonal degeneration. In somecases, NAMPT can extend the lifespan of human smooth muscle cells. Forexample, it has been demonstrated that replicative senescence of smoothmuscle cells was preceded by a marked decline in the expression andactivity of NAMPT. Furthermore, reducing NAMPT activity with theantagonist FK866 induced premature senescence in smooth muscle cells,assessed by serial quantification of the proportion of cells withsenescence-associated beta-galactosidase activity. In contrast,introducing the NAMPT gene into aging human smooth muscle cells delayedsenescence and substantially lengthened cell lifespan, together withenhanced resistance to oxidative stress. NAMPT mediated smooth musclecells lifespan extension was associated with increased activity of theNAD+-dependent longevity enzyme SIRT1 and was abrogated inNAMPT-overexpressing cells transduced with a dominant-negative form ofSIRT1 (H363Y). NAMPT overexpression also reduced the fraction of p53that was acetylated on lysine 382, a target of SIRT1, suppressed anage-related increase in p53 expression, and increased the rate of p53degradation. Moreover, add-back of p53 with recombinant adenovirusblocked the anti-aging effects of NAMPT. These data indicate that NAMPTis a longevity protein that can add stress-resistant life to humansmooth muscle cells by optimizing SIRT1-mediated p53 degradation.

In some embodiments, overexpression of NAMPT increases SIRT1 activityand can protect cells from death due to PARP overexpression, which isconsistent with the hypothesis that NAMPT is a functional equivalent ofPnc1 in mammals. Pnc1 is a stress- and calorie-responsive longevity genethat catalyzes the first and rate-limiting step in NAD+ biosynthesisfrom nicotinamide in yeast.

NAMPT expression and mitochondrial NAD+ levels increase in vivo afterfasting.

In some embodiments, a NAMPT activator is used to treat muscle wastingin a mammal. There are many diseases and conditions which cause adecrease in muscle mass, known as atrophy, including: inactivity, asseen when a cast is put on a limb, or upon extended bedrest (which canoccur during a prolonged illness); cachexia—which is a syndrome that isa co-morbidity of cancer and congestive heart failure; chronicobstructive pulmonary disease; burns, liver failure, and the wastingDejerine-Sottas syndrome (HMSN Type III). Glucocorticoids, a class ofmedications used to treat allergic and other inflammatory conditions caninduce muscle atrophy by increasing break-down of muscle proteins. Othersyndromes or conditions which can induce skeletal muscle atrophy areliver disease, and starvation.

Examples of diseases affecting the nerves that control muscles include,but are not limited to, Amyotrophic lateral sclerosis (ALS, or LouGehrig disease), damage to a single nerve, such as carpal tunnelsyndrome, Guillain-Barre syndrome, nerve damage caused by injury,diabetes, toxins, or alcohol, polio (poliomyelitis), spinal cord injury.

Other causes of muscle atrophy may include: burns, long-termcorticosteroid therapy, malnutrition, muscular dystrophy, and otherdiseases of the muscle, osteoarthritis, rheumatoid arthritis.

Amyotrophic lateral sclerosis (ALS) is a debilitating disordercharacterized by rapidly progressive motor neuron degeneration, whichresults into weakness, muscle atrophy and spasticity. Familial ALS(FALS) is caused by mutations of several genes including SOD1 (type-1superoxide dismutase). Although SOD1 mutations account for only 20% ofFALS and about 2% of sporadic ALS, SOD1 mutant mice recapitulate severalfeatures of human ALS, and are widely employed as model for ALS. Thevalidity of this model is strengthened by the evidence that SOD1aggregates are detected in the spinal cord of people with sporadic ALSor with ALS caused by mutations of genes other than SOD1. The mechanismsby which SOD1 misfolding damages motor neurons are only partiallyelucidated and involve glutamate excitotoxicity, mitochondrialdysfunction, disruption of axonal transport, and abnormalities inastrocytes and microglia. In some embodiments, the NAMPT activatorsdescribed herein are useful for treating ALS.

Neurodegenerative Disorder

Death of nerve cells is the key mechanism in many highly destructiveneurological diseases for which there are limited treatment optionsexist. Understanding the molecular networks linking these diseases couldfacilitate the discovery of novel diagnostics and therapeutics. NAD isan essential metabolite for many cellular functions including energyproduction, protein deacetylation, calcium signaling, and DNA repair.With many different processes dependent on this molecule, the loss ofNAD could cause problems in neurons of the brain with age. It was shownthat NAMPT levels and therefore NAD levels decline in the brains of micewith age. Supplementation with an NAD precursor was able to restore NADlevels, enhancing regeneration in the brains of aged mice. Compoundsthat work as activators of NAMPT in cells were found to prevent newbornneuron death and enhanced neurogenesis and preserved cognitive functionin aged rodents upon their prolonged administration. In addition totheir efficacy in animal models of Alzheimer's disease, NAMPT activatorswere found to be effective in other models of neurological disordersincluding Parkinson's disease, amyotrophic lateral sclerosis,depression, Down syndrome, and neonatal nerve injury. Since NAMPTactivators elevate NAD levels through activation of NAMPT, it is likelythat this pathway is responsible for the protective and regenerativeeffects of this drug in the brain.

Alzheimer's disease (AD) accounts for 60% to 70% of cases of dementia.It is a chronic neurodegenerative disease that usually starts slowly andgets worse over time. The most common early symptom is difficulty inremembering recent events (short term memory loss). As the diseaseadvances, symptoms can include: problems with language, disorientation(including easily getting lost), mood swings, loss of motivation, notmanaging self-care, and behavioral issues. As a person's conditiondeclines, she or he often withdraws from family and society. Gradually,bodily functions are lost, ultimately leading to death. Although thespeed of progression can vary, the average life expectancy followingdiagnosis is three to nine years. In some embodiments, the NAMPTactivators described herein are useful for treating Alzheimer's disease.

Huntington's disease (HD) is a neurodegenerative genetic disorder thataffects muscle coordination and leads to mental decline and behavioralsymptoms. Symptoms of the disease can vary between individuals andaffected members of the same family, but usually progress predictably.The earliest symptoms are often subtle problems with mood or cognition.A general lack of coordination and an unsteady gait often follows. Asthe disease advances, uncoordinated, jerky body movements become moreapparent, along with a decline in mental abilities and behavioralsymptoms. Physical abilities gradually worsen until coordinated movementbecomes difficult. Mental abilities generally decline into dementia.Complications such as pneumonia, heart disease, and physical injury fromfalls reduce life expectancy to around twenty years from the point atwhich symptoms begin. Physical symptoms can begin at any age frominfancy to old age, but usually begin between 35 and 44 years of age. Insome embodiments, the NAMPT activators described herein are useful fortreating Huntington's disease.

Parkinson's disease (PD) is a chronic movement disorder resulting from adisturbance in the normal functioning of the basal ganglia, a collectionof subcortical nuclei that are essential for the initiation and controlof motor activity. The underlying pathology of the disease is aprogressive degeneration of the dopaminergic nigrostriatal tract thatmanifests as a range of motor deficits including akinesia orbradykinesia, tremor, rigidity and postural instability. Currenttherapies for PD are essentially based on dopamine replacement andinclude levodapa (L-DOPA), a precursor of dopamine, and dopaminereceptor agonists. These agents are effective in treating the symptomsof the disease in the early stages, but are less effective as thedisease progresses when debilitating side-effects such as “on-off”fluctuations in efficacy and uncontrollable dyskinesias (involuntarymuscle movements) ensue. More importantly, dopaminergic treatments donot halt the disease progression. For these reasons, severalinvestigators have started to focus on nondopaminergic interventions assymptomatic and neuroprotecive strategies in PD. In some embodiments,the NAMPT activators described herein are useful for treatingParkinson's disease.

Compounds

In one aspect, described herein is a compound that has the structure ofFormula (I), or a pharmaceutically acceptable salt, solvate, prodrug, orN-oxide thereof:

-   -   wherein:    -   each R¹ is independently selected from the group consisting of        H, D, C₁-C₄alkyl and C₁-C₄deuteroalkyl;    -   R² is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   R³ is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   or R² and R³ are taken together with the intervening atoms        joining R² and R³ to form a 5- or 6-membered ring;    -   ring A is a monocyclic ring that is a 6-membered heteroaryl, a        5-membered heteroaryl, or phenyl;    -   each R^(a) is independently selected from the group consisting        of H, D, halogen, —CN, —OH, —N(R⁶)₂, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted monocyclic        carbocycle, and substituted or unsubstituted monocyclic        heterocycle;    -   R⁶ is H, D, or substituted or unsubstituted C₁-C₆alkyl;    -   n is 0, 1, 2, 3, or 4;    -   each R⁴ is independently selected from the group consisting of        H, D, halogen, —CN, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, and substituted or        unsubstituted C₁-C₆heteroalkyl;    -   m is 0, 1, 2, 3, or 4;    -   X is absent, —X¹-L¹- or L¹-X¹;    -   X¹ is selected from the group consisting of —O—, —S—, —SO₂—,        —NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —C(═O)—, —OC(═O)NR⁵—, —NR⁵C(═O)O—, and        —NR⁵C(═O)NR⁵—;        -   each R⁵ is independently selected from the group consisting            of H, D, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkyl, substituted or            unsubstituted C₃-C₆cycloalkyl, and substituted or            unsubstituted benzyl;    -   L¹ is absent or substituted or unsubstituted C₁-C₄alkylene;    -   Y is selected from the group consisting of H, D, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted benzyl,        substituted or unsubstituted naphthyl, and substituted or        unsubstituted heteroaryl, wherein if Y is substituted then Y is        substituted with 1-4 R⁷ groups;    -   each R⁷ is independently selected from the group consisting of        D, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹,        —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹,        —NH₂, —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹,        —NR⁸C(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, a        substituted or unsubstituted C₃-C₆cycloalkyl, a substituted or        unsubstituted C₂-C₆heterocycloalkyl, a substituted or        unsubstituted aryl, and a substituted or unsubstituted        heteroaryl;    -   each R⁸ is independently selected from the group consisting of        H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, and C₁-C₆heteroalkyl;    -   each R⁹ is independently selected from the group consisting of        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₆cycloalkyl, a substituted or unsubstituted        C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, a substituted or        unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a        substituted or unsubstituted —C₁-C₄alkylene-aryl, or a        substituted or unsubstituted —C₁-C₄alkylene-heteroaryl;    -   or when R⁸ and R⁹ are attached to the same N atom then R⁸ and R⁹        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle;    -   or when Y and R⁵ are attached to the same N atom then Y and R⁵        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, mis 1 or 2. In other embodiments, m is 0. In some other embodiments, mis 1. In some other embodiments, m is 2.

In some embodiments, each R¹ is H, D, —CH₃, or —CH₂CH₃; R² is H, —CH₃,or —CH₂CH₃; and R³ is H, —CH₃, or —CH₂CH₃.

In some embodiments, R² is H; and R³ is H.

In some embodiments, R² and R³ are taken together with the interveningatoms joining R² and R³ to form an imidazolidin-2-one or atetrahydropyrimidin-2(1H)-one. In some embodiments, R² and R³ are takentogether with the intervening atoms joining R² and R³ to form animidazolidin-2-one.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl or a 1,3-relationshipon the phenyl.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl.

In some embodiments, ring A is a 6-membered heteroaryl, or a 5-memberedheteroaryl.

In some embodiments, ring A is a 6-membered heteroaryl that is selectedfrom pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

In some embodiments, ring A is a 6-membered heteroaryl that is selectedfrom pyridin-4-yl, pyridin-3-yl, and pyridin-2-yl.

In some embodiments,

In some embodiments, ring A is a 5-membered heteroaryl containing 1-4 Natoms and 0 or 1 O or S atom, or a monocyclic heterocycle containing 0-4N atoms and 1 O or S atoms.

In some embodiments, ring A is a 5-membered heteroaryl that is selectedfrom the group consisting of furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, and thiadiazolyl.

In some embodiments,

In another aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein:    -   each R¹ is independently selected from the group consisting of        H, D, C₁-C₄alkyl and C₁-C₄deuteroalkyl;    -   R² is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   R³ is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   or R² and R³ are taken together with the intervening atoms        joining R² and R³ to form a 5- or 6-membered ring;

is a monocyclic 5-membered heteroaryl that is

-   -   each R^(a) is independently selected from the group consisting        of H, D, halogen, —CN, —OH, —N(R⁶)₂, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted monocyclic        carbocycle, and substituted or unsubstituted monocyclic        heterocycle;    -   R⁶ is H, D, or substituted or unsubstituted C₁-C₆alkyl;    -   n is 0, 1, 2, 3, or 4;    -   or R^(a) and R³ are taken together with the intervening atoms        joining R^(a) and R³ to form a 5- or 6-membered ring;    -   each R⁴ is independently selected from the group consisting of        H, D, halogen, —CN, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, and substituted or        unsubstituted C₁-C₆heteroalkyl;    -   m is 0, 1, 2, 3, or 4;    -   X is absent or -L¹-X¹-L²-;    -   L¹ is absent or —CH₂—;    -   X¹ is selected from the group consisting of —S—, —SO₂—, —NR⁵—,        —SO₂NR⁵—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,        —C(═O)—, —OC(═O)NR⁵—, —NR⁵C(═O)O—, and —NR⁵C(═O)NR⁵—;        -   each R⁵ is independently selected from the group consisting            of H, D, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆deuteroalkyl, substituted            or unsubstituted C₁-C₆fluoroalkyl, substituted or            unsubstituted C₃-C₆cycloalkyl, and substituted or            unsubstituted benzyl;    -   L² is absent or substituted or unsubstituted C₁-C₄alkylene;    -   Y is selected from the group consisting of H, D, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted benzyl,        substituted or unsubstituted naphthyl, and substituted or        unsubstituted heteroaryl, wherein if Y is substituted then Y is        substituted with 1-4 R⁷ groups;    -   each R⁷ is independently selected from the group consisting of        D, —CN, —OH, —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹,        —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹,        —NH₂, —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹,        —NR⁸C(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        a substituted or unsubstituted C₃-C₆cycloalkyl, a substituted or        unsubstituted C₂-C₆heterocycloalkyl, a substituted or        unsubstituted aryl, and a substituted or unsubstituted        heteroaryl;    -   each R⁸ is independently selected from the group consisting of        H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, and C₁-C₆heteroalkyl;    -   each R⁹ is independently selected from the group consisting of        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₆cycloalkyl, a substituted or unsubstituted        C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, a substituted or        unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a        substituted or unsubstituted —C₁-C₄alkylene-aryl, and a        substituted or unsubstituted —C₁-C₄alkylene-heteroaryl;    -   or when R⁸ and R⁹ are attached to the same N atom then R⁸ and R⁹        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle;    -   or when Y and R⁵ are attached to the same N atom then Y and R⁵        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl or a 1,3-relationshipon the phenyl.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl.

In some embodiments, each R¹ is H, D, —CH₃, or —CH₂CH₃; R² is H, —CH₃,or —CH₂CH₃; and R³ is H, —CH₃, or —CH₂CH₃.

In some embodiments, R² is H; and R³ is H.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II), or a pharmaceutically acceptable salt, solvate, prodrug,or N-oxide thereof, wherein:

In some embodiments, the compound of Formula (I) has the structure ofFormula (III), or a pharmaceutically acceptable salt, solvate, prodrug,or N-oxide thereof, wherein:

In another aspect, described herein is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, prodrug, or N-oxide thereof:

-   -   wherein:    -   each R¹ is independently selected from the group consisting of        H, D, C₁-C₄alkyl and C₁-C₄deuteroalkyl;    -   R² is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   R³ is H, D, substituted or unsubstituted C₁-C₆alkyl or        substituted or unsubstituted C₁-C₆deuteroalkyl;    -   or R² and R³ are taken together with the intervening atoms        joining R² and R³ to form a 5- or 6-membered ring;    -   each R^(a) is independently selected from the group consisting        of H, D, halogen, —CN, —OH, —N(R⁶)₂, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted monocyclic        carbocycle, and substituted or unsubstituted monocyclic        heterocycle;    -   R⁶ is H, D, or substituted or unsubstituted C₁-C₆alkyl;    -   n is 0, 1, 2, 3, or 4;    -   or R^(a) and R³ are taken together with the intervening atoms        joining R^(a) and R³ to form a 5- or 6-membered ring;    -   each R⁴ is independently selected from the group consisting of        H, D, halogen, —CN, —OH, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆alkoxy,        substituted or unsubstituted C₁-C₆fluoroalkyl, substituted or        unsubstituted C₁-C₆fluoroalkoxy, and substituted or        unsubstituted C₁-C₆heteroalkyl;    -   m is 0, 1, 2, 3, or 4;    -   X is absent or -L¹-X¹-L²-;    -   L¹ is absent or —CH₂—;    -   X¹ is selected from the group consisting of —O—, —S—, —SO₂—,        —NR⁵—, —SO₂NR⁵—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—, —C(═O)O—,        —OC(═O)O—, —C(═O)—, —OC(═O)NR⁵—, —NR⁵C(═O)O—, and —NR⁵C(═O)NR⁵—;    -   each R⁵ is independently selected from the group consisting of        H, D, substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₃-C₆cycloalkyl,        and substituted or unsubstituted benzyl;    -   L² is absent or substituted or unsubstituted C₁-C₄alkylene;    -   Y is selected from the group consisting of H, D, substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆deuteroalkyl, substituted or unsubstituted        C₁-C₆fluoroalkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted phenyl, substituted or unsubstituted benzyl,        substituted or unsubstituted naphthyl, and substituted or        unsubstituted heteroaryl, wherein if Y is substituted then Y is        substituted with R⁷;    -   R⁷ is selected from the group consisting of D, —CN, —OH, —OR⁹,        —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹, —S(═O)₂NH₂,        —S(═O)₂NR⁸R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹, —NH₂,        —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹,        —NR⁸C(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        C₁-C₃alkyl, C₁-C₆deuteroalkyl, C₁-C₄fluoroalkyl, substituted or        unsubstituted C₁-C₆heteroalkyl, a substituted or unsubstituted        C₃-C₆cycloalkyl, a substituted or unsubstituted        C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl, and        a substituted or unsubstituted heteroaryl;    -   each R⁸ is independently selected from the group consisting of        H, C₁-C₆alkyl, C₁-C₆fluoroalkyl, and C₁-C₆heteroalkyl;    -   each R⁹ is independently selected from the group consisting of        C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, a substituted or        unsubstituted C₃-C₆cycloalkyl, a substituted or unsubstituted        C₂-C₆heterocycloalkyl, a substituted or unsubstituted aryl, a        substituted or unsubstituted heteroaryl, a substituted or        unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted or        unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a        substituted or unsubstituted —C₁-C₄alkylene-aryl, and a        substituted or unsubstituted —C₁-C₄alkylene-heteroaryl;    -   or when R⁸ and R⁹ are attached to the same N atom then R⁸ and R⁹        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle;    -   or when Y and R⁵ are attached to the same N atom then Y and R⁵        are taken together with the N atom to which they are attached to        form a substituted or unsubstituted C₂-C₁₀heterocycle;    -   provided that Y is substituted when R⁵ is H.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl or a 1,3-relationshipon the phenyl.

In some embodiments, the groups

and —X—Y are in a 1,4-relationship on the phenyl.

In some embodiments, each R¹ is H, D, —CH₃, or —CH₂CH₃; R² is H, —CH₃,or —CH₂CH₃; and R³ is H, —CH₃, or —CH₂CH₃.

In some embodiments, R² is H; and R³ is H.

In some embodiments, the compound of Formula (IV) has the structure ofFormula (V), or a pharmaceutically acceptable salt, solvate, prodrug, orN-oxide thereof, wherein:

In some embodiments, each R^(a) is independently selected from the groupconsisting of H, D, F, Cl, Br, —CN, —OH, —NH₂, —NH(CH₃), —N(CH₃)₂, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, and —OCF₃; eachR⁴ is independently selected from the group consisting of H, D, F, Cl,Br, —CN, —OH, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, and —OCF₃.

In some embodiments, each R^(a) is H.

In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1,or 2. In some embodiments, n is 0 or 1.

In some embodiments, n is 0.

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (IIa), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (IIIa), or a pharmaceutically acceptable salt, or solvatethereof, wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (Va), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

In some embodiments, the compound of Formula (Ia) has the structure ofFormula (Va), or a pharmaceutically acceptable salt, or solvate thereof,wherein:

In some embodiments, L² is absent, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or—CH₂CH₂CH₂CH₂—.

In some embodiments, L² is absent or —CH₂—.

In some embodiments, L² is absent.

In some embodiments, X¹ is selected from the group consisting of —S—,—SO₂—, —NR⁵—, —SO₂NR⁵—, —C(═O)NR⁵—, and —C(═O)O—.

In some embodiments, X is —SO₂—.

In some embodiments, L¹ is absent.

In some embodiments, X¹ is selected from the group consisting of —SO₂—,—NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—, —C(═O)NR⁵—, and —NR⁵C(═O)—.

In some embodiments, each R⁵ is independently selected from the groupconsisting of H, C₁-C₄alkyl, and substituted or unsubstituted benzyl; L²is absent or —CH₂—; or when Y and R⁵ are attached to the same N atomthen Y and R⁵ are taken together with the N atom to which they areattached to form a substituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, each R⁵ is H.

In some embodiments, X is absent or -L¹-X¹-L²-; L¹ is absent; X¹ isselected from the group consisting of —SO₂—, —NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—,—C(═O)NR⁵—, and —NR⁵C(═O)—; each R⁵ is independently selected from thegroup consisting of H, C₁-C₄alkyl, and substituted or unsubstitutedbenzyl; L² is absent or —CH₂—; or when Y and R⁵ are attached to the sameN atom then Y and R⁵ are taken together with the N atom to which theyare attached to form a substituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, X is absent or -L¹-X¹-L²-; L¹ is absent; X¹ isselected from the group consisting of —SO₂—, —NH—, —SO₂NH—, and —NHSO₂—;L² is absent or —CH₂—.

In some embodiments, X is absent, —SO₂—, —SO₂CH₂—, —NH—, —NHCH₂—,—SO₂NH—, —SO₂NHCH₂—, —NHSO₂— or —NHSO₂CH₂—.

In some embodiments, X is absent, —SO₂—, —NH—, —SO₂NH—, —SO₂NHCH₂—,—NHSO₂— or —NHSO₂CH₂—.

In some embodiments, X is —SO₂—.

In some embodiments, Y is selected from the group consisting of H, D,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted phenyl, substitutedor unsubstituted benzyl, and substituted or unsubstituted monocyclicheteroaryl, wherein if Y is substituted then Y is substituted with R⁷;or when Y and R⁵ are attached to the same N atom then Y and R⁵ are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, Y is selected from the group consisting of H, D,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆deuteroalkyl, substituted or unsubstituted C₁-C₆fluoroalkyl, andsubstituted or unsubstituted C₁-C₆heteroalkyl, wherein if Y issubstituted then Y is substituted with R⁷.

In some embodiments, Y is selected from the group consisting ofsubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C₂-C₆heterocycloalkyl, substituted or unsubstitutedphenyl, substituted or unsubstituted benzyl, and substituted orunsubstituted monocyclic heteroaryl, wherein if Y is substituted then Yis substituted with R⁷.

In some embodiments, Y is a substituted or unsubstituted phenyl, whereinif Y is substituted then Y is substituted with R⁷.

In some embodiments, Y is selected from the group consisting ofsubstituted or unsubstituted cyclopropyl, substituted or unsubstitutedcyclobutyl, substituted or unsubstituted cyclopentyl, and substituted orunsubstituted cyclohexyl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.

In some embodiments, Y is a substituted or unsubstituted monocyclic6-membered heteroaryl containing 1-3 N atoms, wherein if Y issubstituted then Y is substituted with 1-2 R⁷ groups.

In some embodiments, Y is a substituted or unsubstituted monocyclic5-membered C₁-C₄heteroaryl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.

In some embodiments, Y is selected from the group consisting ofsubstituted or unsubstituted furanyl, substituted or unsubstitutedthienyl, substituted or unsubstituted pyrrolyl, substituted orunsubstituted oxazolyl, substituted or unsubstituted thiazolyl,substituted or unsubstituted imidazolyl, substituted or unsubstitutedpyrazolyl, substituted or unsubstituted triazolylene, substituted orunsubstituted tetrazolyl, substituted or unsubstituted isoxazolyl,substituted or unsubstituted isothiazolyl, substituted or unsubstitutedoxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted orunsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl,substituted or unsubstituted pyrazinyl, substituted or unsubstitutedpyridazinyl, and substituted or unsubstituted triazinyl, wherein if Y issubstituted then Y is substituted with 1-2 R⁷ groups.

In some embodiments, Y is selected from the group consisting ofsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstitutedtetrahydrofuranyl, substituted or unsubstituted dihydrofuranyl,substituted or unsubstituted tetrahydrothienyl, substituted orunsubstituted oxazolidinonyl, substituted or unsubstitutedtetrahydropyranyl, substituted or unsubstituted dihydropyranyl,substituted or unsubstituted tetrahydrothiopyranyl, substituted orunsubstituted piperidinyl, substituted or unsubstituted morpholinyl,substituted or unsubstituted thiomorpholinyl, substituted orunsubstituted thioxanyl, substituted or unsubstituted piperazinyl,substituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted oxetanyl, substituted orunsubstituted thietanyl, substituted or unsubstituted homopiperidinyl,substituted or unsubstituted oxepanyl, substituted or unsubstitutedthiepanyl, substituted or unsubstituted oxazepinyl, substituted orunsubstituted diazepinyl, substituted or unsubstituted thiazepinyl, andsubstituted or unsubstituted 1,2,3,6-tetrahydropyridinyl, wherein if Yis substituted then Y is substituted with 1-2 R⁷ groups.

In some embodiments, X is absent or -L¹-X¹-L²-; L¹ is absent or —CH₂—;X¹ is selected from the group consisting of —NR⁵—, —SO₂NR⁵—, —C(═O)NR⁵—,—OC(═O)NR⁵—, and —NRC(═O)NR⁵—; each R⁵ is independently selected fromthe group consisting of H, D, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆deuteroalkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, and substituted or unsubstituted benzyl; L² is absent;Y and R⁵ are taken together with the N atom to which they are attachedto form a substituted or unsubstituted C₂-C₁₀heterocycle.

In some embodiments, Y and R⁵ are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycle that is a substituted or unsubstituted monocyclicC₂-C₁₀heterocycle, or a substituted or unsubstituted bicyclicC₅-C₁₀heterocycle.

In some embodiments, Y and R⁵ are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycle that is a substituted or unsubstituted monocyclicC₂-C₁₀heterocycle, substituted or unsubstituted fused bicyclicC₅-C₁₀heterocycle, substituted or unsubstituted bridged bicyclicC₅-C₁₀heterocycle, or substituted or unsubstituted spiro bicyclicC₅-C₁₀heterocycle.

In some embodiments, Y and R⁵ are taken together with the N atom towhich they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycle that is selected from a substituted or unsubstitutedβ-lactam, substituted or unsubstituted γ-lactam, substituted orunsubstituted δ-lactam or substituted or unsubstituted ε-lactam.

In some embodiments, Y and R⁵ are taken together with the N atom towhich they are attached to form substituted or unsubstituted aziridinyl,substituted or unsubstituted azetidinyl, substituted or unsubstitutedpyrrolidinyl, substituted or unsubstituted piperidinyl, substituted orunsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl,substituted or unsubstituted piperazinyl, substituted or unsubstitutedazepanyl, substituted or unsubstituted indolinyl, substituted orunsubstituted isoindolinyl, substituted or unsubstitutedtetrahydroquinolinyl, substituted or unsubstitutedtetrahydroisoquinolinyl, or substituted or unsubstituted8-oxa-3-azabicyclo[3.2.1]oct-3-yl.

In some embodiments, described herein is a compound that has thefollowing structure:

or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof.

In some embodiments, described herein is a compound that has thefollowing structure:

-   -   wherein

X and Y are as described in Table 1;

-   -   or a pharmaceutically acceptable salt, solvate, prodrug, or        N-oxide thereof.

In some embodiments, described herein is a compound that has thefollowing structure:

or a pharmaceutically acceptable salt, solvate, prodrug, or N-oxidethereof.

In some embodiments, described herein is a compound that has thefollowing structure:

-   -   wherein    -   R^(a), X and Y are as described in Table 2;

In some embodiments, X and Y are as described in Tables 1 to 5.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Exemplary compounds include the compounds described in the followingTables:

TABLE 1

X Y Compound Name

4-C(═O)O— Et Ethyl 4-(3-((1H-pyrazol-4- yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-(oxazol-4- ylmethyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((3,5-dimethylisoxazol-4-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate

4-C(═O)NH—

N-(3-Chloro-phenyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]- benzamide

4-C(═O)NH—

4-(3-((1H-pyrazol-4- yl)methyl)ureido)-N-(2- methoxyphenyl)benzamide

4-C(═O)NH—

4-(3-((1H-pyrazol-4- yl)methyl)ureido)-N-(2- chlorophenyl)benzamide

4-C(═O)NH—

4-(3-((1H-pyrazol-4- yl)methyl)ureido)-N-(4- methoxyphenyl)benzamide

4-C(═O)NH—

4-(3-((1H-pyrazol-4- yl)methyl)ureido)-N-(4- chlorophenyl)benzamide

4-C(═O)NH—

4-(3-((1H-pyrazol-4- yl)methyl)ureido)-N-(3- methoxyphenyl)benzamide

4-C(═O)O— Et Ethyl 4-(3-(oxazol-5- ylmethyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((3-amino-1H-pyrazol-4-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1H-imidazol-5- yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1-methyl-1H-pyrazol-5-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1H-imidazol-4- yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1H-pyrazol-3- yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((3-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1-(4-methoxybenzyl)- 1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1H-1,2,3-triazol-4- yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1-methyl-1H-imidazol-5-yl)methyl)ureido)benzoate

4-C(═O)O— Et Ethyl 4-(3-((1-methyl-1H-imidazol-4-yl)methyl)ureido)benzoate

4-SO₂NH—

4-[3-(1H-Pyrazol-4-ylmethyl)- ureido]-N-pyridin-2-yl- benzenesulfonamide

4-SO₂NH—

N-Benzyl-4-[3-(1H-pyrazol-4- ylmethyl)-ureido]- benzenesulfonamide

4-SO₂—

1-[4-(3,4-Dihydro-1H-isoquinoline- 2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

4-SO₂—

1-[4-(8-Oxa-3-aza- bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)- urea

4-SO₂NH—

N-Cyclobutylmethyl-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH— Ph N-Phenyl-4-[3-(1H-pyrazol-4- ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NMe—

N-Cyclopentyl-N-methyl-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂N^(i)Pr—

N-Benzyl-N-isopropyl-4-(3-oxazol- 5-ylmethyl-ureido)- benzenesulfonamide

4-SO₂N^(i)Pr—

N-Benzyl-N-isopropyl-4-(3-thiazol- 5-ylmethyl-ureido)-benzenesulfonamide

4-SO₂N^(i)Pr—

N-Benzyl-N-isopropyl-4-(3-thiazol- 2-ylmethyl-ureido)-benzenesulfonamide

4-SO₂N^(i)Pr—

N-Benzyl-N-isopropyl-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂—

1-[4-(3,4-Dihydro-1H-isoquinoline- 2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

4-SO₂NH—

N-(3-Methoxy-benzyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH—

N-(2-Chloro-benzyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH—

N-(2-Methoxy-benzyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH—

N-(4-Methoxy-benzyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH—

N-(4-Chloro-benzyl)-4-[3-(1H- pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

4-SO₂NH—

N-Benzyl-4-(3-oxazol-5-ylmethyl- ureido)-benzenesulfonamide

4-SO₂—

1-[4-(3,4-Dihydro-1H-isoquinoline- 2-sulfonyl)-phenyl]-3-thiazol-5-ylmethyl-urea

4-SO₂—

1-[4-(3,4-Dihydro-1H-isoquinoline- 2-sulfonyl)-phenyl]-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-urea

4-SO₂—

1-[4-(3-Chloro-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)- urea

4-SO₂—

1-[4-(2-Chloro-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)- urea

4-SO₂—

1-[4-(4-Chloro-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)- urea

4-SO₂—

1-[4-(2-Methoxy-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

4-SO₂—

1-[4-(3-Methoxy-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

4-SO₂— Ph 1-(4-Benzenesulfonyl-phenyl)-3- oxazol-5-ylmethyl-urea

4-SO₂— Ph 1-(4-Benzenesulfonyl-phenyl)-3- (1H-pyrazol-4-ylmethyl)-urea

4-SO₂—

1-[4-(4-Methoxy-benzenesulfonyl)- phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

4-NHSO₂— Ph N-[4-(3-Oxazol-5-ylmethyl-ureido)-phenyl]-benzenesulfonamide

4-NHSO₂—

N-Oxazol-5-ylmethyl-2-(4- phenylmethanesulfonylamino-cyclohexa-1,5-dienyl)-acetamide

4-NHSO₂— Ph N-{4-[3-(1H-Pyrazol-4-ylmethyl)- ureido]-phenyl}-benzenesulfonamide

4-NHSO₂—

N-(4-(3-((1H-pyrazol-4- yl)methyl)ureido)phenyl)-1-phenylmethanesulfonamide

4-NHSO₂— Ph N-(4-{3-[1-(4-Methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-ureido}- phenyl)-benzenesulfonamide

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 1.

TABLE 2

R^(a) X Y Compound Name H — 4-F 1-(4-Fluorophenyl)-3-(pyridin-4-ylmethyl)urea H — 4-Cl 1-(4-Chlorophenyl)-3-(pyridin-4- ylmethyl)urea H— 4-Me 1-(Pyridin-4-ylmethyl)-3-(p-tolyl)urea H 2-C(═O)O— Et Ethyl2-(3-(pyridin-4- ylmethyl)ureido)benzoate H 3-C(═O)O— Et Ethyl3-(3-(pyridin-4- ylmethyl)ureido)benzoate H — 4-CF₃1-(Pyridin-4-ylmethyl)-3-(4- (trifluoromethyl)phenyl)urea H — 4-OCF₃1-(Pyridin-4-ylmethyl)-3-(4- (trifluoromethoxy)phenyl)urea H 4-CH₃1-(4-Methoxyphenyl)-3-(pyridin-4- ylmethyl)urea H 4-C(═O)NEt— EtN,N-diethyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NH—p-tolyl 4-(3-(Pyridin-4-ylmethyl)ureido)-N-(p- tolyl)benzamide H4-C(═O)NMe— p-tolyl N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide H 4-C(═O)NH— PhN-phenyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NMe— EtN-ethyl-N-methyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NMe— n-Pr N-methyl-N-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-hydroxyethylN-(2-hydroxyethyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— n-butyl N-butyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— cyclopentyl N-cyclopentyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)O— Et Ethyl 4-(3-(pyridin-4-ylmethyl)ureido)benzoate 2-amino 4-C(═O)O— Et Ethyl4-(3-((2-aminopyridin-4- yl)methyl)ureido)benzoate 2-methoxy 4-C(═O)O—Et Ethyl 4-(3-((2-methoxypyridin-4- yl)methyl)ureido)benzoate 3-methyl4-C(═O)O— Et Ethyl 4-(3-((3-methylpyridin-4- yl)methyl)ureido)benzoate3-amino 4-C(═O)O— Et Ethyl 4-(3-((3-aminopyridin-4-yl)methyl)ureido)benzoate 2-methyl 4-C(═O)O— Et Ethyl4-(3-((2-methylpyridin-4- yl)methyl)ureido)benzoate 2-chloro 4-C(═O)O—Et Ethyl 4-(3-((2-chloropyridin-4- yl)methyl)ureido)benzoate 3-chloro4-C(═O)O— Et Ethyl 4-(3-((3-chloropyridin-4- yl)methyl)ureido)benzoate2-fluoro 4-C(═O)O— Et Ethyl 4-(3-((2-fluoropyridin-4-yl)methyl)ureido)benzoate 3-fluoro 4-C(═O)O— Et Ethyl4-(3-((3-fluoropyridin-4- yl)methyl)ureido)benzoate H 4-C(═O)O— H4-(3-(Pyridin-4- ylmethyl)ureido)benzoic acid H 3-C(═O)O— H3-(3-(Pyridin-4- ylmethyl)ureido)benzoic acid H 4-C(═O)NH— H4-(3-(Pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NH— n-propylN-propyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NH—isopropyl N-Isopropyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NMe— Me N,N-dimethyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 2-morpholinoethyl N-(2-morpholinoethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— cyclohexylN-cyclohexyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NH—2-(piperidin-1-yl)ethyl N-(2-(piperidin-1-yl)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH—2-(pyrrolidin-1-yl)ethyl 4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide H 4-C(═O)NH− isobutylN-isobutyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)NH—cyclobutyl N-cyclobutyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— cyclopropylmethyl N-(cyclopropylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— tetrahydrofuran-3-yl4-(3-(pyridin-4-ylmethyl)ureido)-N- (tetrahydrofuran-3-yl)benzamide H4-C(═O)NH— 2-methoxyethyl N-(2-methoxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— phenethylN-phenethyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)—morpholin-4-yl 1-(4-(Morpholine-4-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea H 4-C(═O)— 4-methylpiperazin-1-yl1-(4-(4-Methylpiperazine-1- carbonyl)phenyl)-3-(pyriidn-4- ylmethyl)ureaH 4-C(═O)— piperidin-1-yl 1-(4-(Piperidine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea H 4-C(═O)— pyrrolidin-1-yl1-(Pyridin-4-ylmethyl)-3-(4- (pyrrolidine-1-carbonyl)phenyl)urea H4-C(═O)NH— cyclopentylmethyl N-(cyclopentylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)— 8-oxa-3-1-(4-(8-Oxa-3-azabicyclo[3.2.1]octane- azabicyclo[3.2.1]octan-3-carbonyl)phenyl)-3-(pyridin-4- 3-yl ylmethyl)urea H 4-C(═O)NH—pyridin-4-ylmethyl N-(pyridin-4-ylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-methylphenethylN-(4-methylphenethyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 4-fluorophenethyl N-(4-fluorophenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 3-ethoxypropylN-(3-ethoxypropyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 2-(dimethylamino)ethyl N-(2-(dimethylamino)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-chlorobenzylN-(2-chlorobenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-chlorobenzyl N-(3-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-methoxybenzylN-(2-methoxybenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-methoxybenzyl N-(3-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-methoxybenzylN-(4-methoxybenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 2-fluorobenzyl N-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 3-fluorobenzylN-(3-fluorobenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 2-methylbenzyl N-(2-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-methylbenzylN-(4-methylbenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-methylbenzyl N-(3-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-chlorobenzylN-(4-chlorobenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 4-fluorobenzyl N-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NMe— benzylN-benzyl-N-methyl-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H 4-C(═O)—isoindolin-2-yl 1-(4-(Isoindoline-2-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea H 4-C(═O)— 1,2,3,4-1-(Pyridin-4-ylmethyl)-3-(4-(1,2,3,4- tetrahydroisoquinolin-2-tetrahydroisoquinoline-2- yl carbonyl)phenyl)urea H 4-C(═O)NH—4-chlorophenyl N-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-chlorophenylN-(2-chlorophenyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-chlorophenyl N-(3-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-fluorophenylN-(2-fluorophenyl)-4-(3-(pyriidn-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-fluorophenyl N-(3-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-fluorophenylN-(4-fluorophenyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— o-tolyl 4-(3-(Pyridin-4-ylmethyl)ureido)-N-(o-tolyl)benzamide H 4-C(═O)NH— m-tolyl4-(3-(pyridin-4-ylmethyl)ureido)-N-(m- tolyl)benzamide H 4-C(═O)NH—4-(methoxymethyl N-(4-(methoxymethyl)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-methoxyphenylN-(2-methoxyphenyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 3-methoxyphenyl N-(3-methoxyphenyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-methoxyphenylN-(4-methoxyphenyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 2- N-(2-(dimethylamino)phenyl)-4-(3- (dimethylamino)phenyl(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 3-N-(3-(dimethylamino)phenyl)-4-(3- (dimethylamino)phenyl(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-N-(4-(dimethylamino)phenyl)-4-(3- (dimethylamino)phenyl(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2-4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2- (trifluoromethoxy)phenyl(trifluoromethoxy)phenyl)benzamide H 4-C(═O)NH— 3-4-(3-(pyridin-4-ylmethyl)ureido)-N-(3- (trifluoromethoxy)phenyl(trifluoromethoxy)phenyl)benzamide H 4-C(═O)NH— 4-4-(3-(pyridin-4-ylmethyl)ureido)-N-(4- (trifluoromethoxy)phenyl(trifluoromethoxy)phenyl)benzamide H 4-C(═O)NH— 4-ethoxyphenylN-(4-ethoxyphenyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamide H4-C(═O)NH— 4-isopropoxyphenyl N-(4-isopropoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4- Methyl 4-(4-(3-(pyridin-4-(methylcarboxy)phenyl ylmethyl)ureido)benzamido)benzoate H 4-C(═O)NH—4-cyanophenyl N-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 3,4-dimethylphenylN-(3,4-dimethylphenyl)-4-(3-(pyridin- 4-ylmethyl)ureido)benzamide H4-C(═O)NH— 3,4-dimethoxyphenyl N-(3,4-dimethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH—benzo[d][1,3]dioxol-5-yl N-(benzo[d][1,3]dioxol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 4-methoxy-3-N-(4-methoxy-3-methylphenyl)-4-(3- methylphenyl(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— 2,3-N-(2,3-dihydroxybenzo[b][1,4]dioxin-6- dihydrobenzo[b][1,4]diox-yl)-4-(3-(pyridin-4- in-6-yl ylmethyl)ureido)benzamide H 4-C(═O)NH—pyridin-2-yl N-(pyridin-2-yl)-4-(3-(pyridin-4- ylmethyl)ureido)benzamideH 4-C(═O)NH— pyridin-3-yl N-(pyridin-3-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— pyrimidin-5-yl4-(3-(pyridin-4-ylmethyl)ureido)-N- (pyrimidin-5-yl)benzamide H4-C(═O)NH— 3-methylisoxazol-5-yl N-(3-methylisoxazol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide H 4-C(═O)NH— thiophen-2-yl4-(3-(Pyridin-4-ylmethyl)ureido)-N- (thiophen-2-yl)benzamide H 4-SO₂NH—Cyclohexyl N-Cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— HN-(4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— MethylN-Methyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H 4-SO₂NH—Propyl N-Propyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H4-SO₂NH— Isopropyl N-Isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— CyclopropylN-Cyclopropyl-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamide H4-SO₂NH— Cyclobutyl N-Cyclobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— cyclopentylN-cyclopentyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H4-SO₂NH— pyrrolidin-3-yl 4-(3-Pyridin-4-ylmethyl-uerido)-N-pyrrolidin-3-yl-benzenesulfonamide H 4-SO₂NH— 1-Methyl-pyrrolidin-3-ylN-(1-Methyl-pyrrolidin-3-yl)-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— tert-butyl N-(tert-butyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 2-Dimethylamino-ethylN-(2-Dimethylamino-ethyl)-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— CyclopropylmethylN-Cyclopropylmethyl-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— Cyclobutylmethyl N-(Cyclobutylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 2-pyrrolidin-1-yl-ethyl4-(3-Pyriidn-4-ylmethyl-ureido)-N-(2- pyrrolidin-1-yl-ethyl)-benzensulfonamide H 4-SO₂NH— 2-(4-Methyl-piperazin-1-N-[2-(4-Methyl-piperazin-1-yl)-ethyl]- yl)-ethyl4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—2-Morpholin-4-yl-ethyl N-(2-Morpholin-4-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—2-Piperidin-1-yl-ethyl N-(2-Piperidin-1-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— 2-Hydroxy-ethylN-(2-Hydroxy-ethyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— tetrahydro-furan-3-yl 4-(3-Pyridin-4-ylmethyl-ureido)-N-(tetrahydro-furan-3-yl)- benzenesulfonamide H 4-SO₂NH− 2-Methoxy-ethylN-(2-Methoxy-ethyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— 3-Methoxy-propyl N-(3-Methoxy-propyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 1-Ethyl-pyrrolidin-2-N-(1-Ethyl-pyrrolidin-2-ylmethyl)-4-(3- ylmethylpyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— neopentylN-neopentyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H4-SO₂NH— 1-Cyclobutyl-ethyl N-(1-Cyclobutyl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— BenzylN-Benzyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H 4-SO₂NH—2-fluorobenzyl N-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 3-fluorobenzylN-(3-fluorobenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamide H4-SO₂NH— 4-fluorobenzyl N-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 2-Chloro-benzylN-(2-Chloro-benzyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— 3-Chloro-benzyl N-(3-(2-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 4-chlorobenzylN-(4-chlorobenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamide H4-SO₂NH— 2-methoxybenzyl N-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 3-Methoxy-benzylN-(3-Methoxy-benzyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— 4-methoxybenzyl N-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 2-Methyl-benzylN-(2-Methyl-benzyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH— 3-Methyl-benzyl N-(3-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 4-methylbenzylN-(4-methylbenzyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamide H4-SO₂NH— 2-Cyano-benzyl N-(2-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfoanmide H 4-SO₂NH— 3-Cyano-benzylN-(3-Cyano-benzyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamide H4-SO₂NH— 4-cyanobenzyl N-(4-cyanobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NHCH₂— 2-2-{[4-(3-Pyridin-4-ylmethyl-ureido)- (methylcarboxy)phenylbenzenesulfonaylamino]-methyl}- benzoic acid methyl ester H 4-SO₂NHCH₂—3- 3-{[4-(3-Pyridin-4-ylmethyl-ureido)- (methylcarboxy)phenylbenzenesulfonylamino]-methyl}- benzoic acid methyl ester H 4-SO₂NHCH₂—4- 4-{[4-(3-Pyridin-4-ylmethyl-ureido)- (methylcarboxy)phenylbenzenesulfonylamino]-methyl}- benzoic acid methyl ester H 4-SO₂NH—3-trifluoromethyl-benzyl 4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethyl-benzyl)- benzenesulfonamide H 4-SO₂NH—2-trifluoromethyl-benzyl 4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)- benzenesulfonamide H 4-SO₂NH—4-trifluoromethyl-benzyl 4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethyl-benzyl)- benzenesulfonamide H 4-SO₂NH—2-trifluoromethoxy- 4-(3-Pyridin-4-ylmethyl-ureido)-N-(2- benzyltrifluoromethoxy-benzyl)- benzenesulfonamide H 4-SO₂NH—3-trifluoromethoxy- 4-(3-Pyridin-4-ylmethyl-ureido)-N-(3- benzyltrifluoromethoxy-benzyl)- benzenesulfonamide H 4-SO₂NH—4-trifluoromethoxy- 4-(3-Pyridin-4-ylmethyl-ureido)-N-(4- benzyltrifluoromethoxy-benzyl)- benzenesulfonamide H 4-SO₂NH—2-Dimethylamino-benzyl N-(2-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—3-Dimethylamino-benzyl N-(3-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—4-Dimethylamino-benzyl N-(4-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—4-Methanesulfonyl- N-(4-Methanesulfonyl-benzyl)-4-(3- benzylpyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NHCH₂—4-(SO₂N(CH₃)₂)phenyl N,N-dimethyl-4-((4-(3-(pyridin-4-ylmethyl)ureido)phenylsulfonamido)meth- yl)benzenesulfonamide H 4-SO₂NH—4- N-(4-((dimethylamino)methyl)benzyl)- ((dimethylamino)methyl)4-(3-(pyridin-4- benzyl ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH—4-Methoxymethyl- N-(4-Methoxymethyl-benzyl)-4-(3- benzylpyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— 1-phenylethylN-(1-phenylethyl)-4-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamide H4-SO₂NH— Pyridin-4-ylmethyl N-Pyridin-4-ylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 1,2,3,4-tetrahydro-4-(3-Pyridin-4-ylmethyl-ureido)-N- naphthalen-1-yl(1,2,3,4-tetrahydro-naphthalen-1-yl)- benzenesulfonamide H 4-SO₂NMe— MeN,N-Dimethyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H4-SO₂NEt— Et N,N-Diethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— 2-Hydroxy-ethylN-(2-Hydroxy-ethyl)-N-methyl-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— CyclopentylN-Cyclopentyl-N-methyl-4-(3-pyridin- 4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— benzyl N-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-benzenesulfonamide H 4-SO₂NMe— 2-Fluoro-benzylN-(2-Fluoro-benzyl)-N-methyl-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— 2-Chloro-benzylN-(2-Chloro-benzyl)-N-methyl-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂— piperazin-1-yl1-[4-(Piperazine-1-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea H4-SO₂NMe— Cyclobutylmethyl N-Cyclobutylmethyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NMe— CyclohexylN-Cyclohexyl-N-methyl-4-(3-pyridin- 4-ylmethyl-ureido)-benzenesulfonamide H 4- CyclopentylN-Cyclopentyl-N-isobutyl-4-(3-pyridin- SO₂N(isobutyl)-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NEt— CyclopentylN-Cyclopentyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— 2-N-methyl-4-(3-(pyridin-4- (trifluoromethyl)benzyl ylmethyl)ureido)-N-(2-(trifluoromethyl)benzyl)benzenesulfona- mide H 4-SO₂NMe—2-trifluoromethoxy- N-Methyl-4-(3-pyridin-4-ylmethyl- benzylureido)-N-(2-trifluoromethoxy-benzyl)- benzenesulfonamide H 4-SO₂NMe—2-Methoxy-benzyl N-(2-Methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4- BenzylN-Benzyl-N-isopropyl-4-(3-pyridin-4- SO₂N(isopropyl)-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NEt— BenzylN-Benzyl-N-ethyl-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamide H4- Benzyl N-Benzyl-N-cyclopropyl-4-(3-pyridin- SO₂N(cyclopropyl)-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂N(propyl)- BenzylN-Benzyl-N-propyl-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamide H4-SO₂(benzyl)- benzyl N,N-Dibenzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NMe— 2-methyl-benzylN-Methyl-N-(2-methyl-benzyl)-4-(3- pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂N(2,2,2- BenzylN-Benzyl-4-(3-pyridin-4-ylmethyl- trifluoro-ethyl)-ureido)-N-(2,2,2-trifluoro-ethyl)- benzenesulfonamide H 4-SO₂N(benzyl)-phenyl N-Benzyl-N-phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂— pyrrolidin-1-ylPyridin-4-ylmethyl-3-[4-(pyrrolidine-1- sulfonyl)-phenyl]-urea H 4-SO₂—Piperidin-1-yl 1-[4-(Piperidine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-SO₂— Morpholin-4-yl1-[4-(Morpholine-4-sulfonyl)-phenyl]- 3-pyridin-4-ylmethyl-urea H 4-SO₂—4-Methyl-piperazin-1-yl 1-[4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-SO₂— 1,3-Dihydro-isoindol-2-1-[4-(1,3-Dihydro-isoindole-2- ylsulfonyl)-phenyl]-3-pyridin-4-ylmethyl- urea H 4-SO₂— 8-Oxa-3-aza-1-[4-(8-Oxa-3-aza- bicyclo[3.2.1]octane-3-ylbicyclo[3.2.1]octane-3-ylsulfonyl)- phenyl]-3-pyridin-4-ylmethyl-urea H4-SO₂— 3,4-Dihydro-1H- 1-[4-(3,4-Dihydro-1H-isoquinoline-2-isoquinolin-2-yl sulfonyl)-phenyl]-3-pyridin-4-ylmethyl- urea H 4-SO₂—8-Chloro-3,4-dihydro- 1-[4-(8-Chloro-3,4-dihydro-1H- 1H-isoquinolin-2-ylisoquinoline-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea H 4-SO₂—8-trifluoromethyl-3,4- Pyridin-4-ylmethyl-3-[4-(8-dihydro-1H-isoquinolin- trifluoromethyl-3,4-dihydro-1H- 2-ylisoquinoline-2-sulfonyl)-phenyl]-urea H 4-SO₂— 6-trifluoromethyl-3,4-Pyridin-4-ylmethyl-3-[4-(6- dihydro-1H-isoquinolin-trifluoromethyl-3,4-dihydro-1H- 2-ylisoquinoline-2-sulfonyl)-phenyl]-urea H 4-SO₂— 8-Fluoro-3,4-dihydro-1-[4-(8-Fluoro-3,4-dihydro-1H- 1H-isoquinolin-2-ylisoquinoline-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea H 4-SO2—8-Methyl-3,4-dihydro- 1-[4-(8-Methyl-3,4-dihydro-1H- 1H-isoquinolin-2-ylisoquinoline-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea H 4-SO₂—3-Methyl-3,4-dihydro- 1-[4-(3-Methyl-3,4-dihydro-1H- 1H-isoquinolin-2-ylisoquinoline-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea H 4-SO₂NH—phenyl N-Phenyl-4-(3-pyridin-4-ylmethyl- ureido)-benzenesulfonamide H4-SO2NH— 2-Methoxy-phenyl N-(2-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— 3-Methoxy-phenylN-(3-Methoxy-phenyl)-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamideH 4-SO₂NH− 4-Methoxy-phenyl N-(4-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide H 4-SO₂NH— o-tolyl4-(3-Pyridin-4-ylmethyl-ureido)-N-o- tolyl-benzenesulfonamide H 4-SO₂NH—m-tolyl 4-(3-Pyridin-4-ylmethyl-ureido)-N-m- tolyl-benzenesulfonamide H4-SO₂NH— p-tolyl 4-(3-Pyridin-4-ylmethyl-ureido)-N-p-tolyl-benzenesulfonamide H 4-SO₂NH— thiazol-2-yl4-(3-Pyridin-4-ylmethyl-ureido)-N- thiazol-2-yl-benzenesulfonamdie H4-SO₂NH— 4,5-Dimethyl-oxazol-2- N-(4,5-Dimethyl-oxazol-2-yl)-4-(3- ylpyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH—5-Methyl-isoxazol-3-yl N-(5-Methyl-isoxazol-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— pyrimidin-2-yl4-(3-Pyridin-4-ylmethyl-ureido)-N- pyrimidin-2-yl-benzenesulfonamide H4-SO₂NH— 4-Methyl-pyrimidin-2-yl N-(4-Methyl-pyrimidin-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)- benzenesulfonamide H 4-SO₂NH— Pyridin-2-ylN-Pyridin-2-yl-4-(3-pyridin-4- ylmethyl-ureido)-benzenesulfonamide H3-SO₂NH— cyclopentyl N-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 3-SO₂NH— benzylN-benzyl-3-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamide H 3-SO₂—Morpholin-4-yl 1-(3-(morpholinosulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea H 3-SO₂NH— cyclobutylmethylN-(cyclobutylmethyl)-3-(3-(pyridin-4- ylmethyl)ureido)benzenesulfonamideH 3-SO₂NH— phenethyl N-phenethyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide H 4-SO₂NH— 2-chloro-phenyl4-(3-pyridin-4-ylmethyl-ureido)-N-(2- chloro-phenyl)-benzenesuulfonamideH 4-SO₂NH— 3-chloro-phenyl 4-(3-pyridin-4-ylmethyl-ureido)-N-(3-chloro-phenyl)-benzenesulfonamide H 4-SO₂NH— 4-chloro-phenyl4-(3-pyridin-4-ylmethyl-ureido)-N-(4- chloro-phenyl)-benzenesulfonamideH 4-SO₂— 3-Chlorophenyl 1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-SO₂— 4-Chlorophenyl1-[4-(4-Chloro-benzenesulfonyl)- phenyl]-3-pyridin-4-ylmethyl-urea H4-SO₂— 2-Chlorophenyl 1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-SO₂— 2-Methoxyphenyl1-[4-(2-Methoxy-benzenesulfonyl)- phenyl]-3-pyridin-4-ylmethyl-urea H4-SO₂— 3-Methoxyphenyl 1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-SO₂— phenyl1-(4-Benzenesulfonyl-phenyl)-3- pyridin-4-ylmethyl-urea H 4-SO₂— benzyl1-(4-Phenylmethanesulfonyl-phenyl)-3- pyridin-4-ylmethyl-urea H 4-SO₂—4-methoxyphenyl 1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea H 4-NHSO₂— phenylN-[4-(3-Pyridin-4-ylmethyl-ureido)- phenyl]-benzenesulfonamide H4-NHSO₂— 2-methoxyphenyl 2-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide H 4-NHSO₂— 3-methoxyphenyl3-Methoxy-N-[4-(3-pyridin-4-ylmethyl- ureido)-phenyl]-benzenesulfonamideH 4-NHSO₂— 4-methoxyphenyl 4-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide H 4-NHSO₂— 2-chlorophenyl2-Chloro-N-[4-(3-pyridin-4-ylmethyl- ureido)-phenyl]-benzenesulfonamideH 4-NHSO₂— 3-chlorophenyl 3-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide H 4-NHSO₂— 4-chlorophenyl4-Chloro-N-[4-(3-pyridin-4-ylmethyl- ureido)-phenyl]-benzenesulfonamideH 4-NHSO₂— benzyl N-[4-(3-Benzyl-ureido)-phenyl]-C-phenyl-methanesulfonamide H 4-NHSO₂— 2-chlorobenzyl1-(2-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfon- amide H 4-NHSO₂— 3-chlorobenzyl1-(3-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfon- amide H 4-NHSO₂— 4-chlorobenzyl1-(4-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfon- amide H 4-NMeSO₂— benzylN-Methyl-C-phenyl-N-[4-(3-pyridin-4- ylmethyl-ureido)-phenyl]-methanesulfonamide H 4-N(iPr)SO₂— phenyl N-Isopropyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]- benzenesulfonamide H 4-NMeSO₂— phenylN-Methyl-N-[4-(3-pyridin-4-ylmethyl- ureido)-phenyl]-benzenesulfonamideH 4-N(iPr)SO₂— benzyl N-Isopropyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]- methanesulfonamide H 4-CH₂SO₂NH— phenylN-Phenyl-C-[4-(3-pyridin-4-ylmethyl- ureido)-phenyl]-methanesulfonamideH 4-CH₂SO₂NMe— phenyl N-Methyl-N-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]- methanesulfonamide

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 2.

TABLE 3

Compound Structure Compound Name

1-(4-Chlorophenyl)-3-(pyridin-3-ylmethyl)urea

1-(4-Fluorophenyl)-3-(pyridin-2-ylmethyl)urea

1-(4-Chlorophenyl)-3-(pyridin-2-ylmethyl)urea

1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea

1-(Pyridin-2-ylmethyl)-3-(p-tolyl)urea

1-(4-Fluorophenyl)-3-(pyriidn-3-ylmethyl)urea

1-(Pyridin-3-ylmethyl)-3-(p-tolyl)urea

1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-Methoxyphenyl)-3-(pyridin-3-ylmethyl)urea

1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea

1-(4-Methoxyphenyl)-3-(pyridin-2-ylmethyl)urea

Ethyl 4-(3-(pyridin-2-ylmethyl)ureido)benzoate

Ethyl 4-(3-(pyridin-3-ylmethyl)ureido)benzoate

Ethyl 4-(3-(pyridin-4-ylmethyl)thioureido)benzoate

Ethyl 4-(3-benzylureido)benzoate

Ethyl 4-(3-(pyrimidin-5-ylmethyl)ureido)benzoate

Ethyl 4-(3-((1,2,3,4-tetrahydroquinolin-4- yl)methyl)ureido)benzoate

Ethyl 4-(3-(quinolin-4-ylmethyl)ureido)benzoate

Ethyl 4-(3-((3-chloropyridin-4-yl)methyl)ureido)benzoate

Ethyl 4-(3-(pyridazin-4-ylmethyl)ureido)benzoate

3-(3-Benzyl-ureido)-benzoic acid

Methyl 4-(1-methyl-3-(pyridin-4-ylmethyl)ureido)benzoate

N-Benzyl-4-(3-benzyl-ureido)-benzenesulfonamide

1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-urea

1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-2-ylmethyl-urea

Ethyl 6-(3-(pyridin-4-ylmethyl)ureido)nicotinate

Ethyl 5-(3-(pyridin-4-ylmethyl)ureido)picolinate

6-(3-Pyridin-4-ylmethyl-ureido)-nicotinamide

5-(3-(pyridin-4-ylmethyl)ureido)picolinamide

Ethyl 6-(3-(pyridin-4-ylmethyl)ureido)nicotinate

Ethyl 5-(3-(pyridin-4-ylmethyl)ureido)picolinate

6-(3-Pyridin-4-ylmethyl-ureido)-nicotinamide

5-(3-(pyridin-4-ylmethyl)ureido)picolinamide

4-(3-Benzyl-3-methyl-ureido)-benzoic acid ethyl ester

1-[(Pyridin-4-ylmethyl)-carbamoyl]-1H-indazole-5- carboxylic acid ethylester

4-(2-Oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid ethylester

4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 3.

TABLE 4

Compound Structure Compound Name

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-2- ylsulfonyl)phenyl)urea

1-[4-(5-Methyl-pyridine-2-sulfonyl-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2- fluorophenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3- fluorophenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4- fluorophenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-4- ylsulfonyl)phenyl)urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-4- sulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-3- sulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-2- sulfonyl)-phenyl]-urea

1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-(1H- pyrazol-4-ylmethyl)-urea

1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

C-(3-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

C-(2-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

C-(4-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

1-[4-(5-Chloro-pyridin-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

C-(3,4-Dichloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

N-(3-Fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyrimidin-5- ylsulfonyl)phenyl)urea

1-(4-Cyclohexanesulfonyl-phenyl)-3-(1H-pyrazol- 4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-[3,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2- sulfonyl)-phenyl]-urea

1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

N-(4-Methyl-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyridine-3- sulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2- sulfonyl)-phenyl]-urea

1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

of 1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol- 4-ylmethyl)-urea

1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

of 1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyrimidine-2- sulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4- (benzo[d]thiazol-2-yl)phenyl)urea

1-[4-(1H-Indazol-3-yl)-phenyl]-3-(1H-pyrazol-4- ylmethyl)-urea

1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-(1H- pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5- benzylthiazol-2-yl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4- yl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4- (benzo[d]thiazol-2-ylamino)phenyl)urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-m-tolyl-thiazol-2-ylamino)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-p-tolyl-thiazol-2-ylamino)-phenyl]-urea

1-{4-[4-(2-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)urea

1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-{4-[4-(3-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(3-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

1-(4-Benzothiazol-4-yl-phenyl)-3-(1H-pyrazol-4- ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)urea

1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-{4-[4-(2-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-{4-[4-(3-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-{4-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(4-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-(1H- pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-3-ylsulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)urea

1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-chloro-1-methyl-1H-indazol-3-yl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5- phenylthiazol-2-yl)phenyl)urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,4-dimethyl-1H-indazol-3-yl)phenyl)urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(1-pyridin-3-yl-benzenesulfonyl)-phenyl]-urea

1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-(1H- pyrazol-4-ylmethyl)-urea

1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-urea

1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-chloro-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-(6-methoxypyridin-3-yl)phenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 4.

TABLE 5

Compound Structure Compound Name

1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(3-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

1-(4-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

1-(3,4-Dichlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

1-(2-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

1-Oxazol-5-ylmethyl-3-[4-(toluene-4-sulfonyl)- phenyl]-urea

1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-2- ylsulfonyl)phenyl)urea

1-(4-((3-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol- 5-ylmethypurea

1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-4- ylsulfonyl)phenyl)urea

1-(4-((2-Methoxyphenyl)sulfonyl)phenyl)-3- (oxazol-5-ylmethypurea

1-Oxazol-5-ylmethyl-3-[4-(toluene-3-sulfonyl)- phenyl]-urea

1-Oxazol-5-ylmethyl-3-[4-(toluene-2-sulfonyl)- phenyl]-urea

1-[4-(5 -Chloro-pyridine-2-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol- 5-ylmethyl)urea

1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol- 5-ylmethyl)urea

1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol- 5-ylmethyl)urea

1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

1-(Oxazol-5-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-(Oxazol-5-ylmethyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-(4-Cyclohexanesulfonyl-phenyl)-3-oxazol-5- ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(4-((4-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol- 5-ylmethyl)urea

1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)- phenyl]-urea

1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)- phenyl]-urea

1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)- phenyl]-urea

1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(pyrazine-2-sulfonyl)- phenyl]-urea

1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]- 3-oxazol-5-ylmethyl-urea

1-Oxazol-5-ylmethyl-3-[4-(pyrimidine-2- sulfonyl)-phenyl]-urea

1-Oxazol-5-ylmethyl-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

1-[4-(1H-Indazol-3-yl)-phenyl]-3-oxazol-5- ylmethyl-urea

1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(oxazol-5- ylmethyl)urea

1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(Oxazol-5-ylmethyl)-3-(4-((4-phenylthiazol-2- yl)amino)phenyl)urea

1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(oxazol-5- ylmethyl)urea

1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-(4-(Benzo[d]thiazol-2-ylamino)phenyl)-3- (oxazol-5-ylmethyl)urea

1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3- oxazol-5-ylmethyl-urea

1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-(4-Benzothiazol-4-yl-phenyl)-3-oxazol-5- ylmethyl-urea

1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-oxazol- 5-ylmethyl-urea

1-(4-([1,1′-Biphenyl]-3-ylsulfonyl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

1-(Oxazol-5-ylmethyl)-3-(4-((5-phenylthiazol-2- yl)amino)phenyl)urea

1-(Oxazol-5-ylmethyl)-3-(4-((5-phenylthiazol-2- yl)phenyl)urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3- (oxazol-5-ylmethyl)urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 5.

TABLE 6

Compound Structure Compound Name

C-(4-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

C-(4-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

C-(4-Cyclopropyl-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

C-Biphenyl-4-yl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

C-(4-Cyano-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

1-[4-(3-Bromo-benzylsulfanylamino)-phenyl]-3- pyridin-4-ylmethyl-urea

C-(2-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

C-(3-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

N-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-m- tolyl-methanesulfonamide

C-(3-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

N-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p- tolyl-methanesulfonamide

C-(2-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

1-[4-(4-Fluoro-phenylmethanesulfonyl)-phenyl]-3- (1H-pyrazol-4-yl)-urea

1-[4-(2-Methyl-benzylsulfanylamino)-phenyl]-3- pyridin-4-ylmethyl-urea

C-(2-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

1-Pyridin-4-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-Pyridin-4-ylmethyl-3-[4-(toluene-4-sulfonyl)- phenyl]-urea

1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-(4-(Pyridin-2-ylsulfonyl)phenyl)-3-(pyridin-4- ylmethyl)urea

1-(Pyridin-4-ylmethyl)-3-(4-(pyridin-4- ylsulfonyl)phenyl)urea

1-Pyridin-4-ylmethyl-3-[4-(toluene-3-sulfonyl)- phenyl]-urea

1-Pyridin-4-ylmethyl-3-[4-(toluene-2-sulfonyl)- phenyl]-urea

1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin- 4-ylmethyl)urea

1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin- 4-ylmethyl)urea

1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin- 4-ylmethyl)urea

1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

1-(Pyridin-4-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

1-(4-Cyclohexanesulfonyl-phenyl)-3-pyridin-4- ylmethyl-urea

1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

Pyridin-4-ylmethyl-3-[4-(thiazole-2-sulfonyl)- phenyl]-urea

1-Pyridin-4-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

of 1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-Pyridin-4-ylmethyl)-3-(4-(thiazol-5- ylsulfonyl)phenyl)urea

1-[4-(Pyridine-3-sulfonyl)-phenyl]-3-pyridin-4- ylmethyl-urea

1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-pyridin-4- ylmethyl-urea

1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-Pyridin-4-ylmethyl-3-[4-(pyrimidine-2- sulfonyl)-phenyl]-urea

1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4- ylmethyl-urea

1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(pyridin-4- ylmethyl)urea

1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)-3- (pyridin-4-ylmethyl)urea

1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(pyridin-4- ylmethyl)urea

1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-[4-(Benzothiazol-2-ylamino)-phenyl]-3-pyridin- 4-ylmethyl-urea

1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-(4-Benzothiazol-4-yl-phenyl)-3-pyridin-4- ylmethyl-urea

1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-pyridin- 4-ylmethyl-urea

1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-((5-Phenylthiazol-2-yl)amino)phenyl)-3- (pyridin-4-ylmethyl)urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-(4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4- ylmethyl-urea

1-(4-(1,4-Dimethyl-1H-indazol-3-yl)phenyl)-3- (pyridin-4-ylmethyl)urea

1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-pyridin- 4-ylmethyl-urea

1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(2-Pyridin-3-yl-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(2-Pyridin-4-yl-benzenesulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(4′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3- pyridin-4-ylmethyl-urea

1-(4-((2′-Chloro-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-((4′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-((2-(6-Methoxypyridin-3- yl)phenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-((3′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-((2′-Methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(3-Cyano-4-((3,5- difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

1-(4-(5-phenylthiazol-2-yl)phenyl)-3-(pyridin-4- ylmethyl)urea

1-(2-Cyano-4-((3,5- difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

In one aspect, provided herein is a pharmaceutically acceptable salt orsolvate of a compound described in Table 6.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Further Forms of Compounds

In one aspect, the compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va), possesses one or more stereocentersand each stereocenter exists independently in either the R or Sconfiguration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In certainembodiments, compounds described herein are prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds/salts, separating the diastereomers and recovering theoptically pure enantiomers. In some embodiments, resolution ofenantiomers is carried out using covalent diastereomeric derivatives ofthe compounds described herein. In another embodiment, diastereomers areseparated by separation/resolution techniques based upon differences insolubility. In other embodiments, separation of stereoisomers isperformed by chromatography or by the forming diastereomeric salts andseparation by recrystallization, or chromatography, or any combinationthereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In oneaspect, stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

In one aspect, prodrugs are designed to alter the metabolic stability orthe transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacokinetic, pharmacodynamic processes and drug metabolism in vivo,once a pharmaceutically active compound is known, the design of prodrugsof the compound is possible. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401,Rooseboom et al., Pharmacological Reviews, 56:53-102, 2004; Aesop Cho,“Recent Advances in Oral Prodrug Discovery”, Annual Reports in MedicinalChemistry, Vol. 41, 395-407, 2006; T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series).

In some cases, some of the herein-described compounds may be a prodrugfor another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactionsTherefore incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, suchas, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In oneaspect, isotopically-labeled compounds described herein, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. In one aspect, substitution with isotopes such as deuteriumaffords certain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

“Pharmaceutically acceptable” as used herein, refers a material, such asa carrier or diluent, which does not abrogate the biological activity orproperties of the compound, and is relatively nontoxic, i.e., thematerial may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound of Formula (I),(Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) with acids.Pharmaceutically acceptable salts are also obtained by reacting acompound of Formula (I), (Ia), (II), (Ia), (III), (IIIa), (IV), (IVa),(V) or (Va) with a base to form a salt.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein may coordinate with an organicbase, such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein may form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms, particularlysolvates. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and may be formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates ofcompounds described herein can be conveniently prepared or formed duringthe processes described herein. In addition, the compounds providedherein can exist in unsolvated as well as solvated forms. In general,the solvated forms are considered equivalent to the unsolvated forms forthe purposes of the compounds and methods provided herein.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compounds as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein. As a guidethe following synthetic methods may be utilized.

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. A detailed description oftechniques applicable to the creation of protecting groups and theirremoval are described in Greene and Wuts, Protective Groups in OrganicSynthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, andKocienski, Protective Groups, Thieme Verlag, New York, N.Y., 1994, whichare incorporated herein by reference for such disclosure).

In one aspect, compounds are synthesized as described in the Examplessection.

Definitions

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural referents unless the contentclearly dictates otherwise. It should also be noted that the term “or”is generally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radical,having from one to twenty carbon atoms, and which is attached to therest of the molecule by a single bond. An alkyl comprising up to 10carbon atoms is referred to as a C₁-C₁₀ alkyl, likewise, for example, analkyl comprising up to 6 carbon atoms is a C₁-C₆ alkyl. Alkyls (andother moieties defined herein) comprising other numbers of carbon atomsare represented similarly. Alkyl groups include, but are not limited to,C₁-C₁₀ alkyl, C₁-C₉ alkyl, C₁-C₈ alkyl, C₁-C₇ alkyl, C₁-C₆ alkyl, C₁-C₅alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈ alkyl, C₃-C₈ alkyland C₄-C₈ alkyl. Representative alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl,i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, thealkyl is methyl or ethyl. In some embodiments, the alkyl is —CH(CH₃)₂ or—C(CH₃)₃. Unless stated otherwise specifically in the specification, analkyl group may be optionally substituted as described below. “Alkylene”or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group.In some embodiments, the alkylene is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—. Insome embodiments, the alkylene is —CH₂—. In some embodiments, thealkylene is —CH₂CH₂—. In some embodiments, the alkylene is —CH₂CH₂CH₂—.

“Alkoxy” refers to a radical of the formula —OR where R is an alkylradical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed below. Representative alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy, butoxy, pentoxy. In someembodiments, the alkoxy is methoxy. In some embodiments, the alkoxy isethoxy.

“Heteroalkylene” refers to an alkyl radical as described above where oneor more carbon atoms of the alkyl is replaced with a O, N or S atom.“Heteroalkylene” or “heteroalkylene chain” refers to a straight orbranched divalent heteroalkyl chain linking the rest of the molecule toa radical group. Unless stated otherwise specifically in thespecification, the heteroalkyl or heteroalkylene group may be optionallysubstituted as described below. Representative heteroalkyl groupsinclude, but are not limited to —OCH₂OMe, —OCH₂CH₂OMe, or—OCH₂CH₂OCH₂CH₂NH₂. Representative heteroalkylene groups include, butare not limited to —OCH₂CH₂O—, —OCH₂CH₂OCH₂CH₂O—, or—OCH₂CH₂OCH₂CH₂OCH₂CH₂O—.

“Alkylamino” refers to a radical of the formula —NHR or —NRR where eachR is, independently, an alkyl radical as defined above. Unless statedotherwise specifically in the specification, an alkylamino group may beoptionally substituted as described below.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer.Aromatics can be optionally substituted. The term “aromatic” includesboth aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups(e.g., pyridinyl, quinolinyl).

“Aryl” refers to an aromatic ring wherein each of the atoms forming thering is a carbon atom. Aryl groups can be optionally substituted.Examples of aryl groups include, but are not limited to phenyl, andnaphthyl. In some embodiments, the aryl is phenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group). Unless stated otherwise specifically in thespecification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals that are optionallysubstituted.

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to:

and the like.

“Cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical,wherein each of the atoms forming the ring (i.e. skeletal atoms) is acarbon atom. Cycloalkyls may be saturated, or partially unsaturated.Cycloalkyls may be fused with an aromatic ring (in which case thecycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to ten carbon atoms, from three to eight carbon atoms,from three to six carbon atoms, or from three to five carbon atoms.Monocyclic cyclcoalkyl radicals include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Insome embodiments, the monocyclic cyclcoalkyl is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In some embodiments, the monocycliccyclcoalkyl is cyclopentyl. Polycyclic radicals include, for example,adamantyl, norbomyl, decalinyl, and 3,4-dihydronaphthalen-1(2H)-one.Unless otherwise stated specifically in the specification, a cycloalkylgroup may be optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy,2,2,2-trifluoroethoxy, 1,2-difluoroethoxy, 3-bromo-2-fluoropropoxy,1,2-dibromoethoxy, and the like. Unless stated otherwise specifically inthe specification, a haloalkoxy group may be optionally substituted.

“Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” refers to astable 3- to 14-membered non-aromatic ring radical comprising 2 to 10carbon atoms and from one to 4 heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur. Unless stated otherwisespecifically in the specification, the heterocycloalkyl radical may be amonocyclic, or bicyclic ring system, which may include fused (when fusedwith an aryl or a heteroaryl ring, the heterocycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems. The nitrogen,carbon or sulfur atoms in the heterocyclyl radical may be optionallyoxidized. The nitrogen atom may be optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. Examples ofsuch heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes allring forms of carbohydrates, including but not limited tomonosaccharides, disaccharides and oligosaccharides. Unless otherwisenoted, heterocycloalkyls have from 2 to 10 carbons in the ring. In someembodiments, heterocycloalkyls have from 2 to 8 carbons in the ring. Insome embodiments, heterocycloalkyls have from 2 to 8 carbons in the ringand 1 or 2 N atoms. In some embodiments, heterocycloalkyls have from 2to 10 carbons, 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring. Insome embodiments, heterocycloalkyls have from 2 to 10 carbons, 1-2 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. It is understood thatwhen referring to the number of carbon atoms in a heterocycloalkyl, thenumber of carbon atoms in the heterocycloalkyl is not the same as thetotal number of atoms (including the heteroatoms) that make up theheterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).Unless stated otherwise specifically in the specification, aheterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to an aryl group that includes one or more ringheteroatoms selected from nitrogen, oxygen and sulfur. The heteroaryl ismonocyclic or bicyclic. Illustrative examples of monocyclic heteroarylsinclude pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, furazanyl, indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. Illustrative examples of monocyclic heteroaryls includepyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Illustrative examples of bicyclicheteroaryls include indolizine, indole, benzofuran, benzothiophene,indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline,cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, andpteridine. In some embodiments, heteroaryl is pyridinyl, pyrazinyl,pyrimidinyl, thiazolyl, thienyl, thiadiazolyl or furyl. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, a bicyclic heteroaryl is a C₆-C₉heteroaryl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, haloalkyl,cycloalkyl, aryl, heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy,alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone,arylsulfone, —CN, alkyne, C₁-C₆alkylalkyne, halogen, acyl, acyloxy,—CO₂H, —CO₂alkyl, nitro, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. In some embodiments, optional substituents are independentlyselected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, and —CO₂alkyl. In some embodiments,optional substituents are independently selected from fluoro, chloro,bromo, iodo, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments,substituted groups are substituted with one or two of the precedinggroups. In some embodiments, an optional substituent on an aliphaticcarbon atom (acyclic or cyclic, saturated or unsaturated carbon atoms,excluding aromatic carbon atoms) includes oxo (═O).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) and a co-agent, are both administeredto a patient simultaneously in the form of a single entity or dosage.The term “non-fixed combination” means that the active ingredients, e.g.a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV),(IVa), (V) or (Va) and a co-agent, are administered to a patient asseparate entities either simultaneously, concurrently or sequentiallywith no specific intervening time limits, wherein such administrationprovides effective levels of the two compounds in the body of thepatient. The latter also applies to cocktail therapy, e.g. theadministration of three or more active ingredients.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, humans. In one embodiment, the mammalis a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

Administration and Pharmaceutical Composition

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va) with other chemical components (i.e. pharmaceuticallyacceptable inactive ingredients), such as carriers, excipients, binders,filling agents, suspending agents, flavoring agents, sweetening agents,disintegrating agents, dispersing agents, surfactants, lubricants,colorants, diluents, solubilizers, moistening agents, plasticizers,stabilizers, penetration enhancers, wetting agents, anti-foaming agents,antioxidants, preservatives, or one or more combination thereof. Thepharmaceutical composition facilitates administration of the compound toan organism.

Pharmaceutical formulations described herein are administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular, intramedullary injections, intrathecal,direct intraventricular, intraperitoneal, intralymphatic, intranasalinjections), intranasal, buccal, topical or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are administered orally.

In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are administered topically. Insuch embodiments, the compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) is formulated into a variety oftopically administrable compositions, such as solutions, suspensions,lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks,medicated bandages, balms, creams or ointments. In one aspect, thecompounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va) are administered topically to the skin.

In another aspect, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are administered by inhalation.

In another aspect, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are formulated for intranasaladministration. Such formulations include nasal sprays, nasal mists, andthe like.

In another aspect, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are formulated as eye drops.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation to the mammal; and/or (e) administered bynasal administration to the mammal; or and/or (f) administered byinjection to the mammal; and/or (g) administered topically to themammal; and/or (h) administered by ophthalmic administration; and/or (i)administered rectally to the mammal; and/or (j) administerednon-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound ofFormula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va),including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound ofFormula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va),including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

In certain embodiments, the compound of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) is administered in a localrather than systemic manner.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) is administered topically. Insome embodiments, the compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) is administered systemically.

In some embodiments, the pharmaceutical formulation is in the form of atablet. In other embodiments, pharmaceutical formulations of thecompounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va) are in the form of a capsule.

In one aspect, liquid formulation dosage forms for oral administrationare in the form of aqueous suspensions or solutions selected from thegroup including, but not limited to, aqueous oral dispersions,emulsions, solutions, elixirs, gels, and syrups.

For administration by inhalation, a compound of Formula (I), (Ia), (II),(IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is formulated for use asan aerosol, a mist or a powder.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in a conventional manner.

In some embodiments, compounds of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) are prepared as transdermal dosageforms.

In one aspect, a compound of Formula (I), (Ia), (II), (IIa), (III),(IIIa), (IV), (IVa), (V) or (Va) is formulated into a pharmaceuticalcomposition suitable for intramuscular, subcutaneous, or intravenousinjection.

In some embodiments, the compound of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) is be administered topically andcan be formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments.

In some embodiments, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), (Ia), (II), (IIa),(III), (IIIa), (IV), (IVa), (V) or (Va) are used in the preparation ofmedicaments for the treatment of diseases or conditions describedherein. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions that include atleast one compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa),(IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt, activemetabolite, prodrug, or solvate thereof, in therapeutically effectiveamounts to said subject.

In certain embodiments, the compositions containing the compound ofFormula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va)are administered for prophylactic and/or therapeutic treatments. Incertain therapeutic applications, the compositions are administered to apatient already suffering from a disease or condition, in an amountsufficient to cure or at least partially arrest at least one of thesymptoms of the disease or condition. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the patient's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compounds ofFormula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va)are administered to a patient susceptible to or otherwise at risk of aparticular disease, disorder or condition.

In certain embodiments, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”).

Doses employed for adult human treatment are typically in the range of0.01 mg-5000 mg per day or from about 1 mg to about 1000 mg per day. Inone embodiment, the desired dose is conveniently presented in a singledose or in divided doses.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va) in combination with another therapeutic agent.

In one specific embodiment, a compound of Formula (I), (Ia), (II),(IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is co-administered with asecond therapeutic agent, wherein the compound of Formula (I), (Ia),(II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) and the secondtherapeutic agent modulate different aspects of the disease, disorder orcondition being treated, thereby providing a greater overall benefitthan administration of either therapeutic agent alone.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drug(s)employed, on the specific drug(s) employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

If administration is simultaneous, the multiple therapeutic agents are,by way of example only, provided in a single, unified form, or inmultiple forms.

In some embodiments, the one or more agents used in the treatment of ametabolic disorder include, but are not limited to, a statin, an insulinsensitizing drug, (such as sitagliptin, vildagliptin, saxagliptin,linagliptin, anaglptin, teneligliptin, alogliptin, gemiglptin, ordutoglpitin), meglitinide, sulfonylurea, peroxisomeproliferator-activated receptor (alpha-glucosidase inhibitor, amylinagonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor PPAR)-gamma agonist(e.g., a thiazolidinedione (TZD) [such as ioglitazone, rosiglitazone,rivoglitazone, or troglitazone], aleglitazar, farglitazar, muraglitazar,or tesaglitazar), a glucagon-like peptide (GLP) agonist,anti-inflammatory agent (e.g., oral corticosteroid), or a combinationthereof. In some embodiments, the one or more agents used in thetreatment of a metabolic disorder include, but are not limited to, astatin, HMG-CoA reductase inhibitor, fish oil, fibrate, niacin or othertreatment for dyslipidemia. In some embodiments retinoic acid is alsoadministered. In one example, nicotinamide ribonucleoside and/ornicotinamide ribonucleoside analogs are also administered. Nicotinamideribonucleoside and its analogs promote NAD+ production of which is asubstrate for many enzymatic reactions such as p450s.

In some embodiments, the therapy that is used in conjunction with aNAMPT activator includes administration of one or more additionalcompounds or therapies, such as an anti-obesity and/or an anti-diabetestherapy. For example, in some embodiments the disclosed therapiesdescribed herein is provided with a meglitinide, e.g., to stimulate therelease of insulin. Exemplary meglitinides are repaglinide (Prandin) andnateglinide (Starlix). In some embodiments, a therapy described hereinis provided with a sulfonylurea, e.g., to stimulate the release ofinsulin. Exemplary sulfonylureas are glipizide (Glucotrol), glimepiride(Amaryl), and glyburide (DiaBeta, Glynase). In some embodiments, atherapy described herein is provided with a dipeptidyl peptidase-4(DPP-4) inhibitor, e.g., to stimulate the release of insulin and/or toinhibit the release of glucose from the liver. Exemplary dipeptidylpeptidase-4 (DPP-4) inhibitors are saxagliptin (Onglyza), sitagliptin(Januvia), and linagliptin (Tradjenta). In some embodiments, a therapydescribed herein is provided with a biguanide, e.g., to inhibit therelease of glucose from the liver and/or to improve sensitivity toinsulin. An exemplary biguanide is metformin (Fortamet, Glucophage). Insome embodiments, a therapy described herein is provided with athiazolidinedione, e.g., to improve sensitivity to insulin and/or toinhibit the release of glucose from the liver. Exemplarythiazolidinediones include but are not limited to rosiglitazone(Avandia) and pioglitazone (Actos). In some embodiments a therapydescribed herein is provided with an alpha-glucosidase inhibitor, e.g.,to slow the breakdown of starches and some sugars. Exemplaryalpha-glucosidase inhibitors include acarbose (Precose) and miglitol(Glyset). In some embodiments, a therapy as described herein is providedwith an injectable medication such as an amylin mimetic or an incretinmemetic, e.g., to stimulate the release of insulin. An exemplary amylinmimetic is pramlintide (Symlin); exemplary incretin mimetics includeexenatide (Byetta) and liraglutide (Victoza). In some embodiments atherapy described herein is provided with insulin. The technology is notlimited to any particular form of insulin, but encompasses providing thecompounds described with any form of insulin. In some embodiments, thetherapy described is used with an insulin injection. In someembodiments, a therapy described herein is provided with more than oneadditional therapy (e.g., drug or other biologically active compositionor compound), e.g., two, three, four or more compounds.

In some embodiments, a NAMPT activator described herein is used inconjunction with therapy used to treat muscle atrophy. Therapies used totreat muscle atrophy include, but are not limited to, physical therapyprograms, medication, surgery and electrical stimulation. Muscle atrophytreatment medications include, but are not limited to, anti-inflammatorymedication, anabolic steroids, amino acid therapy, selective adrenergicreceptor modulators (SARM).

In some embodiments, a NAMPT activator is used in combination withdonepezil, galantamine, rivastigmine, memantine, latrepirdine,idalopridine, or cerlapirdine.

In some embodiments, a NAMPT activator is used in combination withlevodopa. In some embodiments, a NAMPT activator is used in combinationwith carbidopa-levodopa. In some embodiments, a NAMPT activator is usedin combination with a dopamine agonist, such as ropinirole, pramipexole,or rotigotine. In some embodiments, a NAMPT activator is used incombination with a MAO-B inhibitor such as selegiline or rasagiline. Insome embodiments, a NAMPT activator is used in combination with ananticholinergic such as benztropine or trihexyphenidyl. In someembodiments, the additional therapeutic agent is amantadine.

In some embodiments, a NAMPT activator is used in combination withtetrabenazine, haloperidol, chlorpromazine, risperidone, olanzapine,quetiapine, amantadine, levetiracetam, clonazepam, citalopram,fluoxetine, sertraline, valproate, carbamazepine, or lamotrigine.

In some embodiments, a NAMPT activator is used in combination withriluzole, baclofen, diazepam, trihexyphenidyl or amitriptyline.

In some embodiments, a NAMPT activator is used in combination witharipiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine,paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine,fluphenazine, haloperidol, perphenazine. escitalopram, duloxetine,venlafaxine, or paroxetine, buspirone, or a benzodiazepine, such asalprazolam, chlordiazepoxide, diazepam, or lorazepam.

In some embodiments, a NAMPT activator is used in combination with ananti-cancer therapy. In some embodiments, a NAMPT activator is used incombination with conventional chemotherapy, radiotherapy, hormonaltherapy, and/or immunotherapy. In some embodiments, a NAMPT activator isused in combination with conventional chemotherapeutic agents includingalkylating agents (e.g., temozolomide, cyclophosphamide, ifosfamide,chlorambucil, busulfan, melphalan, mechlorethamine, uramustine,thiotepa, nitrosoureas, etc.), anti-metabolites (e.g., 5-fluorouracil,azathioprine, methotrexate, leucovorin, capecitabine, cytarabine,floxuridine, fludarabine, gemcitabine, pemetrexed, raltitrexed, etc.),plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors(e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposidephosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin,adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), EGFR inhibitors (e.g.,gefitinib, erlotinib, etc.), and the like.

EXAMPLES

The following examples are intended to illustrate but not limit thedisclosed embodiments.

Example 1: Synthesis of 1-(4-Chlorophenyl)-3-(pyridin-3-ylmethyl)urea

Step 1: To a solution of pyridin-3-ylmethanamine (5.0 g, 46.2 mmol) indry DCM (200 mL) was added phenyl chloroformate (8.7 g, 55.4 mmol),followed by triethyl-amine (5.6 g, 55.4 mmol). The resulting mixture wasstirred at room temperature for 0.5 hr. The reaction was monitored byTLC. Then DCM was removed in vacuum to give a residue, which waspurified by a silica gel column eluting with DCM/MeOH=50/1 to affordphenyl (pyridin-3-ylmethyl)carbamate (9.82 g, yield: 93%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.60 (s, 1H), 8.56 (d, J=4.4 Hz,1H), 7.71 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.32-7.27 (m, 1H),7.24-7.18 (m, 1H), 7.17-7.10 (m, 2H), 5.53 (brs, 1H), 4.47 (d, J=6.0 Hz,2H).

Step 2: To a solution of phenyl (pyridin-3-ylmethyl)carbamate (100 mg,0.438 mmol) in dioxane (10 mL) was added 4-chloro-phenylamine (62 mg,0.482 mmol), followed by triethyl-amine (133 mg, 1.31 mmol). Theresulting mixture was stirred at 80° C. overnight. The reaction wasmonitored by TLC. Then the reaction mixture was allowed to cool to roomtemperature and concentrated in vacuum to give a residue, which waspurified by prep-TLC (DCM/MeOH=20/1) to afford1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea (55.4 mg, yield: 48%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.77 (brs, 1H), 8.52 (d, J=2.0Hz, 1H), 8.45 (dd, J=4.8, 1.6 Hz, 1H), 7.74-7.68 (m, 1H), 7.46-7.40 (m,2H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.29-7.23 (m, 2H), 6.75 (t, J=5.6 Hz,1H), 4.31 (d, J=6.0 Hz, 2H). MS: m/z 262.0 (M+H⁺).

Example 2: Synthesis of 1-(4-Fluorophenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.72 (brs, 1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.44-7.38 (m,2H), 7.28 (d, J=5.6 Hz, 2H), 7.10-7.02 (m, 2H), 6.72 (t, J=6.0 Hz, 1H),4.32 (d, J=6.0 Hz, 2H). MS: m/z 246.1 (M+H⁺).

Example 3: Synthesis of 1-(4-Chlorophenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.85 (brs, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.44 (d, J=8.8 Hz,1H), 7.33-7.21 (m, 4H), 6.78 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H).MS: m/z 262.0 (M+H⁺).

Example 4: Synthesis of 1-(Pyridin-4-ylmethyl)-3-(p-tolyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.55 (brs, 1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.28 (d, J=7.6Hz, 4H), 7.03 (d, J=8.0 Hz, 2H), 6.60 (t, J=6.0 Hz, 1H), 4.31 (d, J=6.0Hz, 2H), 2.21 (s, 3H). MS: m/z 242.1 (M+H⁺).

Example 5: Synthesis of 1-(4-Fluorophenyl)-3-(pyridin-2-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.80 (brs, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.81-7.74 (m, 1H),7.45-7.38 (m, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.27 (dd, J=6.8, 5.2 Hz, 1H),7.10-7.02 (m, 2H), 6.73 (t, J=5.6 Hz, 1H), 4.40 (d, J=5.6 Hz, 2H). MS:m/z 245.9 (M+H⁺).

Example 6: Synthesis of 1-(4-Chlorophenyl)-3-(pyridin-2-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.92 (brs, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.80-7.74 (m, 1H),7.48-7.40 (m, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 3H), 6.79 (t,J=5.6 Hz, 1H), 4.40 (d, J=5.6 Hz, 2H). MS: m/z 262.0 (M+H⁺).

Example 7: Synthesis of 1-(Pyridin-2-ylmethyl)-3-(p-tolyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.63 (brs, 1H), 8.52 (d, J=4.8, 1H), 7.76 (dt, J=7.2, 1.6Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.31-7.24 (m, 3H), 7.02 (d, J=8.8 Hz,2H), 6.68 (t, J=5.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 2.21 (s, 3H). MS:m/z 242.1 (M+H⁺).

Example 8: Synthesis of 1-(4-Fluorophenyl)-3-(pyridin-3-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.63 (brs, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.45 (dd, J=4.8, 1.6Hz, 1H), 7.74-7.68 (m, 1H), 7.44-7.32 (m, 3H), 7.09-7.01 (m, 2H), 6.68(t, J=6.0 Hz, 1H), 4.31 (d, J=6.0 Hz, 2H). MS: m/z 246.0 (M+H⁺).

Example 9: Synthesis of 1-(Pyridin-3-ylmethyl)-3-(p-tolyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.52 (d, J=2.0 Hz, 1H), 8.47 (brs, 1H), 8.45 (dd, J=4.8, 1.6Hz, 1H), 7.74-7.68 (m, 1H), 7.35 (dd, J=8.0, 4.8 Hz, 1H), 7.31-7.24 (m,2H), 7.06-6.99 (m, 2H), 6.62 (t, J=6.0 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H),2.21 (s, 3H). MS: m/z 242.1 (M+H⁺).

Example 10: Synthesis of1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=9.07 (brs, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.46 (dd, J=4.8, 1.6Hz, 1H), 7.75-7.69 (m, 1H), 7.64-7.54 (m, 4H), 7.36 (dd, J=8.0, 4.8 Hz,1H), 6.87 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 296.0(M+H⁺).

Example 11: Synthesis of1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.84 (brs, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.45 (dd, J=4.8, 1.6Hz, 1H), 7.75-7.68 (m, 1H), 7.55-7.47 (m, 2H), 7.36 (dd, J=8.0, 4.0 Hz,1H), 7.26-7.19 (m, 2H), 6.77 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H).MS: m/z 312.0 (M+H⁺).

Example 12: Synthesis of 1-(4-Methoxyphenyl)-3-(Pyridin-3-ylmethyl)urea

The title compound was prepared as described in example1-(4-chlorophenyl)-3-(pyridin-3-ylmethyl)urea. ¹H NMR (400 MHz,DMSO-d₆): δ=8.51 (d, J=2.0 Hz, 1H), 8.45 (dd, J=4.8, 1.6 Hz, 1H), 8.38(brs, 1H), 7.73-7.67 (m, 1H), 7.35 (dd, J=7.6, 4.4 Hz, 1H), 7.32-7.26(m, 2H), 6.84-6.78 (m, 2H), 6.58 (t, J=6.0 Hz, 1H), 4.30 (d, J=6.0 Hz,2H), 3.69 (s, 3H). MS: m/z 258.1 (M+H⁺).

Example 13: Synthesis of Ethyl 2-(3-(pyridin-4-ylmethyl)ureido)benzoate

To a solution of 2-amino-benzoic acid ethyl ester (158 mg, 0.96 mmol) inTHF (10 mL) was added triethylamine (316.0 mg, 3.13 mmol) andtriphosgene (118 mg, 0.40 mmol). The mixture was stirred at 40° C. for 1hr. Then 4-(aminomethyl)pyridine (126 mg, 1.17 mmol) was added and themixture was stirred at 40° C. for 4 hrs. After that, the solution waspartitioned between water (10 mL) and EA (10 mL). The aqueous phase wasextracted with EA (20 mL×3). The organic layer was washed with water (20mL×2), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE/EA=1/1) togive ethyl 2-(3-(pyridin-4-ylmethyl)ureido)benzoate (239 mg, yield: 83%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.98 (s, 1H), 8.51 (dd,J=4.8, 1.2 Hz, 2H), 8.35 (d, J=8.8 Hz, 1H), 8.11 (t, J=6.0 Hz, 1H), 7.92(dd, J=8.0, 1.2 Hz, 1H), 7.53-7.49 (m, 1H), 7.31-7.29 (m, 2H), 7.03-6.99(m, 1H), 4.33 (q, J=7.2 Hz, 4H), 1.34 (t, J=7.2 Hz, 3H). MS: m/z 299.9(M+H⁺).

Example 14: Synthesis of Ethyl 3-(3-(pyridin-4-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.02 (s, 1H), 8.51 (d, J=5.6 Hz, 2H), 8.11 (s, 1H), 7.65 (d, J=8.0 Hz,1H), 7.51 (d, J=7.2 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.31 (d, J=7.2 Hz,2H), 6.81 (t, J=6.0 Hz, 1H), 4.36-4.28 (m, 4H). 1.32 (t, J=7.2 Hz, 3H).MS: m/z 300.1 (M+H⁺).

Example 15: Synthesis of1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.22 (s, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.77 (td, J=7.6, 1.6 Hz, 1H),7.61 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.0 Hz, 1H),7.28 (dd, J=7.2, 4.8 Hz, 1H), 6.93 (d, J=5.2 Hz, 1H), 4.43 (d, J=5.6 Hz,2H). MS: m/z 295.9 (M+H⁺).

Example 16: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.15 (s, 1H), 8.50 (dd, J=8.8, 1.6 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H),7.57 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.89 (t, J=6.0 Hz, 1H),4.34 (d, J=6.0 Hz, 2H). MS: m/z 295.8 (M+H⁺).

Example 17: Synthesis of1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea

The title compound was prepare as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.03 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 7.50 (d,J=8.8 Hz, 2H), 7.34 (d, J=7.6 Hz, 1H), 7.30-7.20 (m, 3H), 6.83 (t, J=5.6Hz, 1H), 4.40 (d, J=5.6 Hz, 2H). MS: m/z 311.8 (M+H⁺).

Example 18: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.94 (s, 1H), 8.50 (d, J=5.6 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.28 (d,J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 6.81 (t, J=6.0 Hz, 1H), 4.40 (d,J=6.0 Hz, 2H). MS: m/z 311.8 (M+H⁺).

Example 19: Synthesis of 1-(4-Methoxyphenyl)-3-(pyridin-2-ylmethyl)urea

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.55-8.50 (m, 2H), 7.79-7.75 (m, 1H), 7.36-7.25 (m, 4H), 6.81 (dd,J=8.2, 2.8 Hz, 2H), 6.64 (t, J=7.6 Hz, 1H), 4.40 (d, J=7.6 Hz, 2H), 3.69(s, 3H). MS: m/z 258.1 (M+H⁺).

Example 20: Synthesis of 1-(4-Methoxyphenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.51-8.46 (m, 3H), 7.32-7.26 (m, 4H), 6.81 (d, J=9.2 Hz, 2H), 6.35 (t,J=6.0 Hz, 1H), 4.31 (d, J=6.0 Hz, 2H), 3.69 (s, 3H). MS: m/z 257.9(M+H⁺).

Example 21: Synthesis ofN,N-diethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example2-(3-pyridin-4-ylmethyl-ureido)-benzoic acid ethyl ester. ¹H NMR (400MHz, DMSO-d₆): δ=9.23 (brs, 1H), 8.48 (d, J=8.0 Hz, 2H), 7.47-7.42 (m,2H), 7.29 (d, J=7.6 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.05 (brs, 1H),4.33 (d, J=8.0 Hz, 2H), 3.30-3.25 (4H, m), 1.02 (t, J=7.2 Hz, 6H). MS:m/z 326.9 (M+H⁺).

Example 22: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.96 (d, J=3.2 Hz, 1H), 9.13 (s, 1H), 8.55 (d, J=8.0 Hz, 2H), 7.88 (d,J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.15 (d,J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 6.90 (t, J=6.0 Hz, 1H), 4.37 (t,J=6.0 Hz, 2H), 2.44 (s, 3H). MS: m/z 360.9 (M+H⁺).

Example 23: Synthesis ofN-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.88 (brs, 1H), 8.48 (dd, J=6.4, 2.0 Hz, 2H), 7.27-7.19 (m, 4H),7.13-6.97 (m, 6H), 6.83 (t, J=7.2 Hz, 1H), 4.28 (t, J=7.2 Hz, 2H), 3.31(s, 3H), 2.23 (s, 3H). MS: m/z 375.1 (M+H⁺).

Example 24: Synthesis ofN-phenyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=10.04 (brs, 1H), 9.17 (brs, 1H), 8.52 (d, J=6.0 Hz, 2H), 7.88 (d,J=8.8 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.36-7.30(m, 4H), 7.07 (t, J=7.6 Hz, 1H), 7.00-6.92 (m, 1H), 4.36 (t, J=6.0 Hz,2H). MS: m/z 346.9 (M+H⁺).

Example 25: Synthesis ofN-ethyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.94 (brs, 1H), 8.54 (d, J=4.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.35(d, J=5.6 Hz, 2H), 7.30-7.24 (m, 2H), 6.85-6.82 (m, 1H), 4.36 (t, J=6.0Hz, 2H), 3.37-3.30 (m, 2H), 2.91 (s, 3H), 1.11-1.07 (m, 3H). MS: m/z312.9 (M+H⁺).

Example 26: Synthesis ofN-methyl-N-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.93 (brs, 1H), 8.50 (d, J=5.6 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H),7.31-7.24 (m, 4H), 6.82 (t, J=6.0 Hz, 1H), 4.34 (t, J=6.0 Hz, 2H),3.28-3.15 (m, 2H), 2.91 (s, 3H), 1.60-1.48 (m, 2H), 0.92-0.72 (m, 3H).MS: m/z 326.9 (M+H⁺).

Example 27: Synthesis ofN-(2-hydroxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.99 (brs, 1H), 8.50 (d, J=8.8 Hz, 2H), 8.23 (t, J=6.4 Hz, 1H), 7.74(d, J=9.2 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.29 (d, J=9.2 Hz, 2H), 6.85(t, J=6.4 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.33 (t, J=6.0 Hz, 2H),3.51-3.45 (m, 2H), 3.35-3.25 (m, 2H). MS: m/z 314.9 (M+H⁺).

Example 28: Synthesis ofN-butyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, CD₃OD):δ=8.47-8.46 (m, 2H), 7.74-7.72 (m, 2H), 7.49-7.47 (m, 2H), 7.40-7.39 (m,2H), 4.46 (s, 2H), 3.37-3.35 (m, 1H), 3.31-3.29 (m, 2H), 1.60-1.57 (m,2H), 1.43-1.39 (m, 2H), 0.98-0.94 (m, 2H). MS: m/z 326.9 (M+H⁺).

Example 29: Synthesis ofN-cyclopentyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in example ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, CD₃OD):δ=8.47-8.46 (m, 2H), 7.74-7.72 (m, 2H), 7.49-7.46 (m, 2H), 7.40-7.38 (m,2H), 4.86 (s, 2H), 4.45-4.26 (m, 1H), 2.03-1.99 (m, 2H), 1.78-1.75 (m,2H), 1.65-1.56 (m, 4H). MS: m/z 338.9 (M+H⁺).

Example 30: Synthesis of Ethyl 4-(3-(pyridin-2-ylmethyl)ureido)benzoate

Step 1: The solution of phenyl chroloformate (6.88 g, 43.9 mmol) andpyridine (6.42 g, 81.3 mmol) in THF (100 mL) was degassed and purgedwith N₂. The mixture was stirred at 0° C. for a while. Then4-amino-benzoic acid ethyl ester (6.60 g, 40.0 mmol) was added and themixture was stirred at room temperature for overnight. After that, thesolution was partitioned between water (100 mL) and EA (100 mL). Theaqueous phase was extracted with EA (100 mL×3). The organic layer waswashed with water (100 mL×2), dried over Na₂SO₄, and concentrated underreduced pressure to give ethyl 4-((phenoxycarbonyl)amino)benzoate (14.27g, crude) as a white solid. MS: m/z 285.9 (M+H⁺).

Step 2: To a solution of 4-phenoxycarbonylamino-benzoic acid ethyl ester(576 mg, 2.02 mmol) in MeCN (8 mL), was added DMAP (242 mg, 1.95 mmol)and 2-(aminomethyl)pyridine (230 mg, 2.13 mmol). The mixture wasrefluxed at 80° C. for overnight. After that, the solution waspartitioned between water (20 mL) and EA (20 mL). The aqueous phase wasextracted with EA (20 mL×3). The organic layer was washed with water (20mL×2), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (EA) to giveethyl 4-(3-(pyridin-2-ylmethyl)ureido)benzoate (42 mg, yield: 10%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.23 (s, 1H), 8.53 (d, J=4.0Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.4Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 4.42 (d, J=5.6 Hz, 2H),4.26 (d, J=7.2 Hz, 4H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 299.9 (M+H⁺).

Example 31: Synthesis of Ethyl 4-(3-(pyridin-3-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.07 (s, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.46 (dd, J=4.8, 1.2 Hz, 1H),7.84 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H),7.38-7.35 (m, 1H), 6.87 (s, 1H), 4.34 (d, J=5.6 Hz, 2H), 4.26 (q, J=7.2Hz, 2H). 1.30 (t, J=7.2 Hz, 3H). MS: m/z 299.9 (M+H⁺).

Example 32: Synthesis of Ethyl 4-(3-(pyridin-4-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.16 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.53 (d,J=8.8 Hz, 2H), 7.29 (d, J=5.2 Hz, 2H), 6.90 (s, 1H), 4.34 (d, J=5.2 Hz,2H), 4.28 (q, J=6.8 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 299.9(M+H⁺).

Example 33: Synthesis of Ethyl4-(3-(pyridin-4-ylmethyl)thioureido)benzoate

The title compound was prepared as described in example4-(3-pyridin-2-ylmethyl-ureido)-benzoic acid ethyl ester. ¹H NMR (400MHz, DMSO-d₆): δ=10.32 (s, 1H), 8.69 (s, 1H), 8.51 (d, J=6.0 Hz, 2H),7.90 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.31 (d, J=6.0 Hz, 2H),4.79 (d, J=5.6 Hz, 2H), 4.28 (q, J=6.8 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).MS: m/z 316.0 (M+H⁺).

Example 34: Synthesis of Ethyl 4-(3-benzylureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.01 (s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.32 (t,J=7.2 Hz, 4H), 7.29 (s, 1H), 6.78 (s, 1H), 4.31 (d, J=6.0 Hz, 2H), 4.26(d, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 299.1 (M+H⁺).

Example 35: Synthesis of Ethyl4-(3-((2-aminopyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.10 (brs, 1H), 7.84 (dd, J=8.8 Hz, 2H), 7.81 (d, J=5.2 Hz, 1H), 7.54(d, J=8.8 Hz, 2H), 6.75 (t, J=5.6 Hz, 1H), 6.39 (dd, J=5.2, 1.2 Hz, 1H),6.33 (s, 1H), 5.87 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 4.16 (d, J=6.4 Hz,2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 315.1 (M+H⁺).

Example 36: Synthesis of Ethyl4-(3-((2-methoxypyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.15 (brs, 1H), 8.09 (dd, J=5.2 Hz, 1H), 7.84 (dd, J=8.8 Hz, 2H), 7.54(d, J=8.8 Hz, 2H), 6.91 (dd, J=5.6, 0.8 Hz, 1H), 6.88 (t, J=6.0 Hz, 1H),6.69 (s, 1H), 4.29 (d, J=5.6 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 3.83 (s,3H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 330.1 (M+H⁺).

Example 37: Synthesis of Ethyl4-(3-(pyrimidin-5-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.36 (brs, 1H), 9.12 (d, J=1.2 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 7.84(d, J=8.8 Hz, 2H), 7.54 (d, J=9.2 Hz, 2H), 7.46 (d, J=5.2 Hz, 1H), 6.99(t, J=6.0 Hz, 1H), 4.42 (d, J=5.6 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30(t, J=6.8 Hz, 3H). MS: m/z 301.0 (M+H⁺).

Example 38: Synthesis of Ethyl4-(3-((3-methylpyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.17 (brs, 1H), 8.36 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 7.84 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.21 (d, J=5.2 Hz, 1H), 6.86 (t, J=6.0Hz, 1H), 4.31 (d, J=5.6 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.28 (s, 3H),1.30 (t, J=7.2 Hz, 3H). MS: m/z 314.0 (M+H⁺).

Example 39: Synthesis of Ehyl4-(3-((3-aminopyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.22 (brs, 1H), 7.94 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.74 (d, J=4.8Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 6.99 (d, J=4.8 Hz, 1H), 6.79 (t, J=6.0Hz, 1H), 5.31 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 4.16 (d, J=6.0 Hz, 2H),1.30 (t, J=7.2 Hz, 3H). MS: m/z 315.0 (M+H⁺).

Example 40: Synthesis of Ethyl4-(3-((2-methylpyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.16 (brs, 1H), 8.36 (d, J=4.8 Hz, 1H), 7.84 (dd, J=7.2, 2.0 Hz, 2H),7.54 (dd, J=7.2, 2.0 Hz, 2H), 7.15 (s, 1H), 7.09 (d, J=4.8 Hz, 1H), 6.89(t, J=6.0 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.44(s, 3H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 314.0 (M+H⁺).

Example 41: Synthesis of Ethyl4-(3-((2-chloropyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.29 (brs, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.54(d, J=8.8 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J=5.2 Hz, 1H), 7.00 (t, J=5.6Hz, 1H), 4.36 (d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2Hz, 3H). MS: m/z 333.9 (M+H⁺).

Example 42: Synthesis of Ethyl4-(3-((1H-pyrazol-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=12.67 (brs, 1H), 8.98 (brs, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.65-7.44 (m,4H), 6.57 (t, J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.16 (d, J=5.6 Hz,2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 289.0 (M+H⁺).

Example 43: Synthesis of Ethyl4-(3-((3-chloropyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.32 (brs, 1H), 8.59 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.84 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 6.96 (t, J=6.0Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2Hz, 3H). MS: m/z 334.0 (M+H⁺).

Example 44: Synthesis of Ethyl4-(3-((2-fluoropyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.29 (brs, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.54(d, J=8.8 Hz, 2H), 7.28 (d, J=4.8 Hz, 1H), 7.05 (s, 1H), 7.01 (t, J=6.0Hz, 1H), 4.39 (d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2Hz, 3H). MS: m/z 318.0 (M+H⁺).

Example 45: Synthesis of Ethyl4-(3-((3-fluoropyridin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.26 (brs, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.40 (d, J=4.4 Hz, 1H), 7.84(d, J=8.8 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.39 (t, J=6.0 Hz, 1H), 6.94(t, J=6.0 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30(t, J=7.2 Hz, 3H). MS: m/z 318.0 (M+H⁺).

Example 46: Synthesis of Ethyl4-(3-(pyridazin-4-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.25 (brs, 1H), 9.18 (s, 1H), 9.15 (dd, J=5.2, 0.8 Hz, 1H), 7.84 (d,J=8.8 Hz, 2H), 7.59-7.50 (m, 3H), 6.96 (t, J=6.0 Hz, 1H), 4.38 (d, J=6.0Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 300.9(M+H⁺).

Example 47: Synthesis of 4-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid

To a solution of ethyl 4-(3-(pyridin-4-ylmethyl)ureido)benzoate (200 mg,0.67 mmol) in CH₃OH (10 mL) was added a solution of NaOH (116 mg, 2.9mmol) in H₂O (10 mL). The resulting mixture was stirred overnight atroom temperature. The mixture was concentrated under reduced pressure.Then HCl (4 M) was dropped into the mixture until pH=5-6. Much solid wasseparated out and filtered to give4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid (117 mg, yield: 64%). ¹HNMR (400 MHz, CF₃CO₂D): δ=8.80 (s, 2H), 8.25-8.19 (m, 4H), 7.55 (s, 2H),4.98 (s, 2H), MS: m/z 271.8 (M+H⁺).

Example 48: Synthesis of 3-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid

The title compound was prepare as described in example4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid. ¹H NMR (400 MHz, CF₃CO₂D):δ=8.90 (d, J=6.8 Hz, 2H), 8.29-8.23 (m, 4H), 7.79 (d, J=7.6 Hz, 1H),7.73 (t, J=7.6 Hz, 1H), 5.06 (s, 2H). MS: m/z 271.9 (M+H⁺).

Example 49: Synthesis of 3-(3-Benzyl-ureido)-benzoic acid

The title compound was prepared as described in example4-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid. ¹H NMR (400 MHz, DMSO-d₆):δ=8.94 (s, 1H), 7.81 (d, J=9.2 Hz, 2H), 7.51-7.49 (m, 2H), 7.34-7.30 (m,4H), 7.24 (s, 1H), 6.76 (s, 1H), 4.31 (d, J=6.0 Hz, 2H). MS: m/z 271.0(M+H⁺).

Example 50: Synthesis of 4-(3-(Pyridin-4-ylmethyl)ureido)benzamide

To a solution of 4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid (55 mg,0.20 mmol) in DMF (3 mL) was added HATU (116 mg, 0.31 mmol), DIPEA(131.00 mg, 1.01 mmol), and the mixture was stirred for 1 hr at roomtemperature. Then NH₄Cl (21.8 mg, 0.41 mmol) was added. The mixture wasstirred overnight at room temperature. The mixture was concentratedunder reduced pressure. The target (17 mg, yield: 31%) was obtained byprep-HPLC as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=5.2Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.49 (d, J=9.6 Hz, 2H), 7.40 (d, J=5.2Hz, 2H), 4.46 (s, 2H). MS: m/z 271.3 (M+H⁺).

Example 51: Synthesis of Methyl4-(1-methyl-3-(pyridin-4-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, CD3OD):δ=8.44-8.43 (m, 2H), 8.07-8.05 (m, 2H), 7.45-7.43 (m, 2H), 7.34-7.32 (m,2H), 4.36 (s, 2H), 3.89 (s, 3H), 3.31-3.29 (s, 3H). MS: m/z 300.0(M+H⁺).

Example 52: Synthesis ofN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

Step 1: To a solution of 4-amino-benzoic acid ethyl ester (500 mg, 3.03mmol) in DCM (10 mL) was added phenyl carbonchloridate (570 mg, 3.63mmol), followed by TEA (926 mg, 9.09 mmol). The resulting mixture wasstirred at room temperature for 1 hour. The reaction was monitored byTLC. Then the mixture was concentrated in vacuum to give a residue,which was purified by a silica gel column eluting with DCM to affordethyl 4-((phenoxycarbonyl)amino)benzoate (826 mg, yield: 96%) as a whitesolid.

Step 2: To a solution of ethyl 4-((phenoxycarbonyl)amino)benzoate (826mg, 2.89 mmol) in ACN (40 mL) was added c-Pyridin-3-yl-methylamine (376mg, 3.47 mmol), followed by DMAP (424 mg, 3.47 mmol). The resultingmixture was stirred at 80° C. overnight. The reaction was monitored byLC-MS. Then the mixture was concentrated in vacuum to give a residue,which was purified by a reversed-phase column (5-95% CAN in H₂O) toafford ethyl 4-(3-(pyridin-4-ylmethyl)ureido)benzoate (786 mg, yield:91%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.18 (brs, 1H), 8.51(dd, J=4.4, 1.6 Hz, 2H), 7.84 (dd, J=7.2, 1.6 Hz, 2H), 7.54 (dd, J=7.2,1.6 Hz, 2H), 7.29 (dd, J=4.0, 1.6 Hz, 2H), 6.90 (t, J=6.0 Hz, 1H), 4.34(d, J=6.0 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

Step 3: To a solution of ethyl 4-(3-(pyridin-4-ylmethyl)ureido)benzoate(12.76 g, 42.6 mmol) in THF/H2O (100 mL+30 mL) was added LiOH (5.37 g,127.8 mmol). The resulting mixture was stirred at room temperatureovernight. The reaction was monitored by TLC. Then THF was removed invacuum to give an aqueous residue, which was acidified to pH=4˜5 withconc. HCl. The solid precipitated from the mixture was filtered. Thecake was washed with H2O (50 mL×3) and dried in air to afford4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid (10.2 g, yield: 88%) aswhite solid.

Step 4: To a solution of 4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid(100 mg, 0.369 mmol) in DMF (8 mL) was added HATU (154 mg, 0.406 mmol)and DIEA (143 mg, 1.107 mmol). The mixture was stirred at roomtemperature for 30 mins. Then propylamine (24 mg, 0.406 mmol) was addedinto the reaction mixture. The resulting reaction mixture was stirred atroom temperature overnight. The reaction was monitored by LC-MS. Thenthe mixture was concentrated in vacuum to give a residue, which waspurified by a reversed-phase column (5-95% ACN in H2O) to affordN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide (90.4 mg, yield: 78%)as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=8.98 (brs, 1H), 8.50 (dd,J=4.4, 1.6 Hz, 2H), 8.25 (t, J=5.6 Hz, 1H), 7.74 (d, J=9.2 Hz, 2H), 7.46(d, J=8.8 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 6.85 (t, J=6.0 Hz, 1H), 4.34(d, J=6.4 Hz, 2H), 3.24-3.14 (m, 2H), 1.57-1.45 (m, 2H), 0.88 (t, J=7.6Hz, 3H). MS: m/z 312.9 (M+H⁺).

Example 53: Synthesis ofN-Isopropyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.48-8.46 (m, 2H), 7.74 (d, J=6.8 Hz, 2H), 7.48 (d, J=6.8 Hz,2H), 7.39 (d, J=5.6 Hz, 2H), 4.46 (s, 2H), 4.20-4.16 (m, 1H), 1.23 (d,J=6.4 Hz, 6H). MS: m/z 313.1 (M+H⁺).

Example 54: Synthesis ofN,N-dimethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.94 (brs, 1H), 8.51 (d, J=3.2 Hz, 2H), 7.46 (d, J=8.0 Hz,2H), 7.37-7.25 (m, 4H), 6.88-6.77 (m, 1H), 4.35 (d, J=5.6 Hz, 2H), 2.95(s, 6H). MS: m/z 298.9 (M+H⁺).

Example 55: Synthesis ofN-(2-morpholinoethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.02 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.20 (t, J=5.6Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.29 (d, J=5.6Hz, 2H), 6.88 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.63-3.52 (m,4H), 3.40-3.29 (m, 2H), 2.47-2.42 (m, 2H), 2.41-2.36 (m, 4H). MS: m/z384.1 (M+H⁺).

Example 56: Synthesis ofN-cyclohexyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.98 (brs, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H), 7.98 (d, J=8.0Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.29 (d, J=6.0Hz, 2H), 6.83 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.80-3.66 (m,1H), 1.86-1.67 (m, 4H), 1.65-1.55 (m, 1H), 1.34-1.22 (m, 4H), 1.18-1.05(m, 1H). MS: m/z 353.1 (M+H⁺).

Example 57: Synthesis ofN-(2-(piperidin-1-yl)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.48 (brs, 1H), 9.26 (brs, 1H), 8.80 (d, J=6.8 Hz, 2H), 8.57(t, J=5.2 Hz, 1H), 7.82 (d, J=6.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.52(d, J=8.8 Hz, 2H), 7.40 (t, J=6.0 Hz, 1H), 4.54 (d, J=5.6 Hz, 2H),3.64-3.57 (m, 2H), 3.57-3.48 (m, 2H), 3.27-3.16 (m, 2H), 3.00-2.85 (m,2H), 1.88-1.76 (m, 2H), 1.74-1.58 (m, 3H), 1.45-1.34 (m, 1H). MS: m/z382.2 (M+H⁺).

Example 58: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(Pyrrolidin-1-yl)ethyl)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.59 (brs, 1H), 9.42 (brs, 1H), 8.77 (d, J=6.8 Hz, 2H), 8.54(t, J=5.6 Hz, 1H), 7.83-7.73 (m, 4H), 7.52 (d, J=9.2 Hz, 2H), 7.32 (t,J=5.6 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.69-3.60 (m, 2H), 3.59-3.52 (m,2H), 3.36-3.28 (m, 2H), 3.11-2.98 (m, 2H), 2.09-1.95 (m, 2H), 1.92-1.79(m, 2H). MS: m/z 368.1 (M+H⁺).

Example 59: Synthesis ofN-isobutyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.98 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.26 (t, J=6.0Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.29 (d, J=6.0Hz, 2H), 6.84 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.05 (t, J=6.4Hz, 2H), 1.88-1.76 (m, 1H), 0.87 (d, J=6.8 Hz, 6H). MS: m/z 326.9(M+H⁺).

Example 60: Synthesis ofN-cyclobutyl-4-(3-(Pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.00 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.40 (d, J=8.0Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.29 (d, J=6.0Hz, 2H), 6.85 (t, J=6.0 Hz, 1H), 4.46-4.36 (m, 1H), 4.34 (d, J=6.0 Hz,2H), 2.25-2.13 (m, 2H), 2.11-1.98 (m, 2H), 1.71-1.58 (m, 2H). MS: m/z324.9 (M+H⁺).

Example 61: Synthesis ofN-(cyclopropylmethyl)-4-(3-(Pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.00 (brs, 1H), 8.50 (dd, J=4.0, 1.6 Hz, 2H), 8.36 (t, J=5.2Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.30 (dd,J=4.8, 1.6 Hz, 2H), 6.85 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.11(t, J=6.0 Hz, 2H), 1.07-0.96 (m, 1H), 0.45-0.38 (m, 2H), 0.24-0.18 (m,2H). MS: m/z 324.9 (M+H⁺).

Example 62: Synthesis of4-(3-(pyridin-4-ylmethyl)ureido)-N-(tetrahydrofuran-3-yl)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.01 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.31 (d, J=6.4Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.47 (d, J=9.2 Hz, 2H), 7.30 (d, J=6.0Hz, 2H), 6.85 (t, J=6.0 Hz, 1H), 4.48-4.38 (m, 1H), 4.34 (d, J=6.0 Hz,2H), 3.88-3.80 (m, 2H), 3.74-3.66 (m, 1H), 3.58-3.52 (m, 1H), 2.18-2.07(m, 1H), 1.95-1.86 (m, 1H). MS: m/z 340.9 (M+H⁺).

Example 63: Synthesis ofN-(2-methoxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.01 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.31 (t, J=5.2Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.29 (d, J=5.6Hz, 2H), 6.87 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.46-3.42 (m,2H), 3.41-3.37 (m, 2H), 3.26 (s, 3H). MS: m/z 329.1 (M+H⁺).

Example 64: Synthesis ofN-phenethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.99 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 8.38 (t, J=6.0Hz, 1H), 7.72 (d, J=9.2 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 7.33-7.26 (m,4H), 7.26-7.17 (m, 3H), 6.85 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H),3.49-3.41 (m, 2H), 2.82 (t, J=7.6 Hz, 2H). MS: m/z 374.8 (M+H⁺).

Example 65: Synthesis of1-(4-(Morpholine-4-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.98 (brs, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.47 (d, J=8.8 Hz,2H), 7.38-7.24 (m, 4H), 6.85 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H),3.68-3.38 (m, 8H). MS: m/z 341.1 (M+H⁺).

Example 66: Synthesis of1-(4-(4-Methylpiperazine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.98 (brs, 1H), 8.50 (d, J=4.4 Hz, 2H), 7.47 (d, J=8.0 Hz,2H), 7.37-7.20 (m, 4H), 6.85 (t, J=6.0 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H),3.67-3.36 (m, 4H), 2.37-2.22 (m, 4H), 2.18 (s, 3H). MS: m/z 354.1(M+H⁺).

Example 67: Synthesis of1-(4-(Piperidine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.98 (brs, 1H), 8.64-8.36 (m, 2H), 7.46 (d, J=6.4 Hz, 2H),7.38-7.15 (m, 4H), 6.98-6.76 (m, 1H), 4.46-4.21 (m, 2H), 3.68-3.33 (m,4H), 1.72-1.55 (m, 2H), 1.54-1.36 (m, 4H). MS: m/z 339.1 (M+H⁺).

Example 68: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.97 (brs, 1H), 8.50 (dd, J=4.8, 1.2 Hz, 2H), 7.50-7.40 (m,4H), 7.29 (d, J=7.2 Hz, 2H), 6.86 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz,2H), 3.49-3.39 (m, 4H), 1.92-1.74 (m, 4H). MS: m/z 325.1 (M+H⁺).

Example 69: Synthesis ofN-(cyclopentylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.02 (brs, 1H), 8.61-8.39 (m, 2H), 7.58-7.38 (m, 2H),7.37-7.15 (m, 5H), 7.00-6.82 (m, 1H), 4.48-4.20 (m, 2H), 2.92-2.71 (m,3H), 1.83-1.55 (m, 6H), 1.53-1.36 (m, 2H). MS: m/z 353.1 (M+H⁺).

Example 70: Synthesis of1-(4-(8-Oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.47 (dd, J=4.8, 1.6 Hz, 2H), 7.50 (dd, J=6.4, 1.6 Hz, 2H),7.39 (d, J=6.0 Hz, 2H), 7.34 (dd, J=6.4, 2.0 Hz, 2H), 4.46 (s, 2H),4.40-4.16 (m, 3H), 3.59-3.36 (m, 2H), 3.19-3.00 (m, 1H), 1.99-1.79 (m,3H), 1.77-1.55 (m, 1H). MS: m/z 367.1 (M+H⁺).

Example 71: Synthesis ofN-(pyridin-4-ylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.47-8.45 (m, 4H), 7.82 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz,2H), 7.41-7.39 (m, 4H), 4.60 (s, 2H), 4.47 (s, 2H). MS: m/z 362.1(M+H⁺).

Example 72: Synthesis ofN-(4-methylphenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.52-8.50 (m, 2H), 7.76-7.74 (m, 2H), 7.53-7.50 (m, 2H),7.44-7.43 (m, 2H), 7.18-7.12 (m, 4H), 4.50 (s, 2H), 3.60-3.56 (m, J=8.0HZ 2H), 2.91-2.87 (m, J=8.0 HZ, 2H), 2.33 (s, 3H). MS: m/z 388.9 (M+H⁺).

Example 73: Synthesis ofN-(4-fluorophenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.49 (s, 2H), 7.71-7.69 (m, 2H), 7.50-7.43 (m, 4H), 7.27-7.23(m, 2H), 7.02-3.97 (m, 2H), 4.46 (s, 2H), 3.57-3.53 (m, J=8.0 HZ 2H),2.90-2.86 (m, J=8.0 HZ 2H), MS: m/z 392.8 (M+H⁺).

Example 74: Synthesis ofN-(3-ethoxypropyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.47-8.46 (m, 2H), 7.74-7.72 (m, 2H), 7.49-7.47 (m, 2H),7.40-7.39 (m, 2H), 4.46 (s, 2H), 3.54-3.42 (m, 6H), 1.87-1.84 (q′ 2H),1.20-1.16 (m, J=8.0 HZ, 2H). MS: m/z 356.9 (M+H⁺).

Example 75: Synthesis ofN-(2-(dimethylamino)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD₃OD): δ=8.53 (d, J=6.0 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.53-7.51 (m,4H), 4.51 (s, 2H), 3.73 (t, J=6.0 Hz, 2H). 3.40-3.35 (m, 2H), 2.98 (s,6H) MS:m/z 342.1 (M+H⁺).

Example 76: Synthesis ofN-(2-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.90 (s, 1H), 8.88-8.85 (m, 1H), 8.51-8.50 (m, 2H), 7.83-781(m, 2H), 7.51-7.43 (m, 3H), 7.33-7.29 (m, 5H), 6.91-6.88 (m, 1H),4.52-4.50 (s, 2H), 4.35-4.33 (s, 2H). MS: m/z 394.9 (M+H⁺).

Example 77: Synthesis ofN-(3-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.17 (s, 1H), 8.92-8.88 (m, 1H), 8.62-8.60 (m, 2H),7.81-7.78 (m, 2H), 7.51-7.48 (m, 4H), 7.38-7.25 (m, 4H), 7.03-7.00 (m,1H), 4.45-4.40 (s, 4H). MS: m/z 394.9 (M+H⁺).

Example 78: Synthesis ofN-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.03 (s, 1H), 8.68-8.65 (m, 1H), 8.51-8.50 (m, 2H),7.82-7.80 (m, 2H), 7.50-7.48 (m, 2H), 7.30-7.29 (m, 2H), 7.24-7.20 (m,1H), 7.16-7.14 (m, 1H), 6.99-6.91 (m, 1H), 6.89-6.86 (m, 2H), 4.42-4.41(s, 2H), 4.34-4.33 (s, 2H), 3.82 (s, 3H). MS: m/z 391.0 (M+H⁺).

Example 79: Synthesis ofN-(3-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.03 (s, 1H), 8.68-8.65 (m, 1H), 8.51-8.50 (m, 2H),7.82-7.80 (m, 2H), 7.50-7.48 (m, 2H), 7.30-7.29 (m, 2H), 7.24-7.20 (m,1H), 7.16-7.14 (m, 1H), 6.99-6.91 (m, 1H), 6.89-6.86 (m, 2H), 4.42-4.41(s, 2H), 4.34-4.33 (s, 2H), 3.82 (s, 3H). MS: m/z 391.0 (M+H⁺).

Example 80: Synthesis ofN-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.07 (s, 1H), 8.78-8.75 (m, 1H), 8.50-8.49 (m, 2H),7.78-7.76 (m, 2H), 7.49-7.46 (m, 2H), 7.29-7.28 (m, 2H), 7.24-7.21 (m,2H), 6.96-6.93 (m, 1H), 6.88-6.86 (m, 2H), 4.38-4.36 (s, 2H), 4.33-4.32(s, 2H), 3.71 (s, 3H). MS: m/z 391.0 (M+H⁺).

Example 81: Synthesis ofN-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.04 (s, 1H), 8.84-8.81 (m, 1H), 8.51-8.49 (m, 2H),7.81-7.79 (m, 2H), 7.50-7.48 (m, 2H), 7.36-7.32 (m, 4H), 7.30-7.14 (m,2H), 6.90-6.87 (m, 1H), 4.49-4.48 (s, 2H), 4.34-4.33 (s, 2H). MS: m/z379.0 (M+H⁺).

Example 82: Synthesis ofN-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.05 (s, 1H), 8.90-8.87 (m, 1H), 8.51-8.49 (m, 2H),7.80-7.78 (m, 2H), 7.50-7.48 (m, 2H), 7.39-7.33 (m, 2H), 7.30-7.11 (m,1H), 7.09-7.04 (m, 3H), 6.91-6.88 (m, 1H), 4.46-4.45 (s, 2H), 4.34-4.33(s, 2H). MS: m/z 379.0 (M+H⁺).

Example 83: Synthesis ofN-(2-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD3OD): δ=8.37-8.35 (m, 2H), 7.69-7.67 (m, 2H), 7.40-7.38 (m, 2H),7.29-7.28 (m, 2H), 7.17-7.14 (m, 1H), 7.05-7.04 (m, 3H), 4.77 (s, 2H),4.45-4.35 (s, 2H), 2.25 (s, 3H). MS: m/z 375.0 (M+H⁺).

Example 84: Synthesis ofN-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.03 (s, 1H), 8.81-8.78 (m, 1H), 8.51-8.49 (m, 2H),7.79-7.77 (m, 2H), 7.49-7.47 (m, 2H), 7.30-7.28 (m, 2H), 7.19-7.12 (m,2H), 7.12-7.10 (m, 2H), 6.90-6.87 (m, 1H), 4.40-4.39 (m, 2H), 4.34-4.32(m, 2H), 2.26 (s, 3H). MS: m/z 375.0 (M+H⁺).

Example 85: Synthesis ofN-(3-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.02 (s, 1H), 8.83-8.80 (s, 1H), 8.51-8.50 (m, 2H),7.81-7.78 (m, 2H), 7.49-7.47 (m, 2H), 7.30-7.28 (m, 2H), 7.21-7.18 (m,1H), 7.08-7.03 (m, 3H), 6.88-6.85 (m, 1H), 4.42-4.40 (s, 2H), 4.34-4.33(s, 2H), 2.27 (s, 3H). MS: m/z 375.0 (M+H⁺).

Example 86: Synthesis ofN-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,CD3OD): δ=8.46 (s, 2H), 7.79-7.77 (m, 2H), 7.50-7.49 (m, 2H), 7.39 (m,2H), 7.31 (m, 4H), 4.52 (s, 2H), 4.45 (s, 2H). MS: m/z 395.0 (M+H⁺).

Example 87: Synthesis ofN-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=9.02 (s, 1H), 8.87-8.84 (s, 1H), 8.51-8.50 (m, 2H),7.80-7.78 (m, 2H), 7.49-7.47 (m, 2H), 7.35-7.28 (s, 4H), 7.16-7.12 (s,2H), 6.88-6.85 (m, 1H), 4.43-4.42 (s, 2H), 4.34-4.33 (s, 2H). MS: m/z379.0 (M+H⁺).

Example 88: Synthesis ofN-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.96 (s, 1H), 8.50-8.49 (m, 2H), 7.47-7.27 (m, 11H),6.85-6.82 (m, 1H), 4.60-4.59 (s, 2H), 4.33-4.32 (s, 2H), 2.86 (s, 3H).MS: m/z 375.0 (M+H⁺).

Example 89: Synthesis of1-(4-(Isoindoline-2-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.97 (s, 1H), 8.52-8.50 (m, 2H), 7.55-7.49 (m, 4H),7.39-7.38 (m, 1H), 7.30-7.27 (m, 5H), 6.86-6.83 (m, 1H), 4.85-4.83 (s,4H), 4.36-4.34 (s, 2H). MS: m/z 373.0 (M+H⁺).

Example 90: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)urea

The title compound was prepared as described in exampleN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400 MHz,DMSO-d₆): δ=8.97 (s, 1H), 8.51-8.50 (m, 2H), 7.50-7.48 (m, 2H),7.36-7.34 (m, 2H), 7.30-7.29 (m, 2H), 7.17 (m, 4H), 6.85-6.82 (m, 1H),4.67 (s, 2H), 4.35-4.33 (s, 2H), 3.67 (s, 2H), 2.87-2.84 (m, 2H). MS:m/z 387.0 (M+H⁺).

Example 91: Synthesis ofN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

Step 1: A mixture of 4-nitrobenzoic acid (4.0 g, 24 mmol), (COCl)₂ (3.3g, 26 mmol) and DMF (2 drops) in DCM (50 mL) was stirred until themixture became clear. The mixture was concentrated in vacuum. Theresidue was added to a mixture of 4-chloroaniline (2.7 g, 22 mmol) andTEA (4.4 g, 44 mmol) and was stirred at room temperature for 16 hrs. Themixture was filtered and the filter cake was dried in vacuum to givecrude N-(4-chlorophenyl)-4-nitrobenzamide (2.8 g, yield: 46%) as ayellow solid, which was used in next step without further purification.

Step 2: A mixture of N-(4-chlorophenyl)-4-nitrobenzamide (2.5 g, 9 mmol)and wet 10% Pd/C (50 mg) in MeOH (50 mL) was stirred at room temperatureunder H2 balloon atmosphere for 2 hrs. The mixture was filtered and thefiltrate was concentrated in vacuum to give crude product (2.0 g, yield:90%) as a white solid, which was used in next step without furtherpurification.

Step 3: A mixture of 4-amino-N-(4-chlorophenyl)benzamide (1.1 g, 4.5mmol), phenyl carbonochloridate (840 mg. 5.4 mmol) and TEA (700 mg, 6.8mmol) in DCM (20 mL) was stirred at room temperature for 1 hr. Themixture was filtered and the filter cake was dried in vacuum to givecrude product (1.1 g, yield: 68%) as a white solid, which was used innext step without further purification.

Step 4: A mixture of phenyl(4-((4-chlorophenyl)carbamoyl)phenyl)carbamate (100 mg, 0.27 mmol),pyridin-4-ylmethanamine (40 mg. 0.37 mmol) and TEA (54 mg, 0.54 mmol) indioxane (5 mL) was stirred at 90° C. for 16 hrs. The mixture wasconcentrated in vacuum and the residue was purified by flashchromatography to giveN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide (25 mg,yield: 25%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=5.6Hz, 2H), 7.87 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.40 (d, J=5.6 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 4.47 (s, 2H).MS: m/z 380.9 (M+H⁺).

Example 92: Synthesis ofN-(2-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.82 (s, 1H), 9.13 (s, 1H), 8.52-8.51 (m, 2H),7.91-7.89 (m, 2H), 7.60-7.53 (m, 4H), 7.39-7.25 (m, 4H), 6.93-6.90 (s,1H), 4.36-4.35 (m, 2H). MS: m/z 380.9 (M+H⁺).

Example 93: Synthesis ofN-(3-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=10.2 (s, 1H), 9.33 (s, 1H), 8.51 (s, 2H),7.98-7.88 (m, 3H), 7.71-7.70 (m, 3H), 7.37-7.34 (m, 3H), 7.14-7.08 (m,2H), 4.35 (s, 2H). MS: m/z 380.9 (M+H⁺).

Example 94: Synthesis ofN-(2-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.90-7.88 (m, 2H), 7.73-7.71 (m,1H), 7.69 (m, 2H), 7.57-7.40 (m, 2H), 7.24-7.17 (m, 3H), 4.47 (s, 2H).MS: m/z 365.0 (M+H⁺).

Example 95: Synthesis ofN-(3-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.8-7.86 (m, 2H), 7.66-7.62 (m,1H), 7.56-7.54 (m, 2H), 7.43-7.40 (m, 3H), 7.35-7.32 (m, 1H), 6.85-6.84(m, 1H), 4.47 (s, 2H). MS: m/z 365.0 (M+H⁺).

Example 96: Synthesis ofN-(4-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. H NMR (400MHz, DMSO-d₆): δ=10.1 (s, 1H), 9.10 (s, 1H), 8.52-8.50 (m, 2H),7.89-7.87 (m, 2H), 7.79-7.76 (m, 2H), 7.56-7.54 (m, 2H), 7.31-7.30 (m,2H), 7.20-7.15 (m, 2H), 6.90 (s, 1H), 4.36-4.34 (m, 2H). MS: m/z 365.0(M+H⁺).

Example 97: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(o-tolyl)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.91-7.89 (m, 2H), 7.56-7.54 (m,2H), 7.41-7.40 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.18 (m, 2H), 4.47 (s,2H), 2.28 (s, 3H). MS: m/z 361.0 (M+H⁺).

Example 98: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(m-tolyl)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.96 (s, 1H), 9.12 (s, 1H), 8.52-8.50 (m, 2H),7.88-7.86 (m, 2H), 7.60 (m, 1H), 7.55-7.53 (m, 3H), 7.31-7.29 (m, 2H),7.22-7.19 (m, 1H), 6.92-6.88 (m, 2H), 4.36-4.34 (s, 2H), 2.30 (s, 3H).MS: m/z 361.0 (M+H⁺).

Example 99: Synthesis ofN-(4-(methoxymethyl)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=10.07 (brs, 1H), 9.32 (brs, 1H), 8.68 (d, J=5.6Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.60 (d, J=6.0Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.15-7.12 (brs,1H), 4.46 (d, J=5.6 Hz, 2H), 4.36 (s, 2H), 3.27 (s, 3H). MS:m/z 391.0(M+H⁺)

Example 100: Synthesis ofN-(2-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.46 (m, 2H), 8.00-7.97 (m, 1H), 7.87-7.84 (m,2H), 7.57-7.54 (m, 2H), 7.41-7.40 (m, 2H), 7.17-7.13 (m, 1H), 7.06-7.04(m, 1H), 6.98-9.94 (m, 1H), 4.47 (s, 2H), 3.91 (s, 3H). MS: m/z 377.0(M+H⁺).

Example 101: Synthesis ofN-(3-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48-8.46 (m, 2H), 7.88-7.85 (m, 2H), 7.55-7.53 (m,2H), 7.41-7.38 (m, 3H), 7.23-7.21 (m, 2H), 6.71-6.68 (m, 1H), 4.47 (s,2H), 3.80-3.29 (s, 3H). MS: m/z 376.8 (M+H⁺).

Example 102: Synthesis ofN-(4-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48-8.47 (m, 2H), 7.87-7.85 (m, 2H), 7.55-7.52 (m,4H), 7.41-7.40 (m, 2H), 6.92-6.90 (m, 2H), 4.47 (s, 2H), 3.79 (s, 3H).MS: m/z 376.9 (M+H⁺).

Example 103: Synthesis ofN-(2-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 8.16-8.14 (m, 1H), 7.87-7.85 (m,2H), 7.59-7.57 (m, 2H), 7.41-7.40 (m, 2H), 7.26 (m, 1H), 7.13-7.11 (m,2H), 4.47 (s, 2H), 2.71 (m, 6H). MS: m/z 390.0 (M+H⁺).

Example 104: Synthesis ofN-(3-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.46 (m, 2H), 7.87-7.85 (m, 2H), 7.54-7.52 (m,2H), 7.41-7.39 (m, 2H), 7.18-7.14 (m, 2H), 7.01-7.00 (m, 1H), 6.99-6.56(m, 1H), 4.47 (s, 2H), 3.03-2.93 (s, 6H). MS: m/z 390.0 (M+H⁺).

Example 105: Synthesis ofN-(3-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.77 (s, 1H), 9.14 (s, 1H), 8.51-8.50 (m, 2H),7.88-7.84 (m, 2H), 7.56-7.51 (m, 4H), 7.30-7.29 (m, 2H), 6.99-6.96 (m,1H), 6.72-6.70 (m, 2H), 4.35-4.33 (s, 2H), 2.86 (s, 6H). MS: m/z 390.0(M+H⁺).

Example 106: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.75-8.74 (m, 2H), 7.99-7.97 (m, 2H), 7.89-7.87 (m,2H), 7.77-7.75 (m, 1H), 7.58-7.56 (m, 2H), 7.39-7.33 (m, 3H), 4.68 (s,2H). MS: m/z 431.0 (M+H⁺).

Example 107: Synthesis of4-(3-(pyridin-4-ylmethyl)ureido)-N-(3-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.86-7.83 (m, 3H), 7.65-7.62 (m,1H), 7.57-7.54 (m, 2H), 7.44-7.40 (m, 3H), 7.03-7.01 (m, 1H), 4.47 (s,2H). MS: m/z 430.9 (M+H⁺).

Example 108: Synthesis of4-(3-(pyridin-4-ylmethyl)ureido)-N-(4-(trifluoromethoxy)phenyl)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.89-7.83 (m, 2H), 7.79-7.77 (m,2H), 7.56-7.54 (m, 2H), 7.41-7.40 (m, 2H), 7.27-7.25 (m, 2H), 4.47 (s,2H). MS: m/z 431.0 (M+H⁺).

Example 109: Synthesis ofN-(4-ethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.92 (s, 1H), 9.09 (s, 1H), 8.52-8.50 (m, 2H),7.87-7.85 (m, 2H), 7.65-7.62 (m, 2H), 7.54-7.52 (m, 2H), 7.31-7.29 (m,2H), 6.91-6.88 (m, 3H), 4.35-4.34 (s, 2H), 4.02-3.97 (q, 2H), 1.31-1.30(t, 3H). MS: m/z 391.0 (M+H⁺).

Example 110: Synthesis ofN-(4-isopropoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepare as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.91 (s, 1H), 9.07 (s, 1H), 8.52-8.50 (m, 2H),7.87-7.85 (m, 2H), 7.63-7.61 (m, 2H), 7.54-7.52 (m, 2H), 7.31-7.29 (m,2H), 6.89-6.87 (m, 3H), 4.57-4.54 (m, 1H), 4.35-4.34 (s, 2H), 1.25-1.24(s, 6H). MS: m/z 405.0 (M+H⁺).

Example 111: Synthesis of Methyl4-(4-(3-(pyridin-4-ylmethyl)ureido)benzamido)benzoate

The title compound was prepared as described in exampleN-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR(400 MHz, DMSO-d₆): δ=10.3 (s, 1H), 9.14 (s, 1H), 8.52-8.50 (m, 2H),7.94-7.89 (m, 6H), 7.57-7.55 (m, 2H), 7.31-7.30 (m, 2H), 6.93-6.90 (m,1H), 4.36-4.34 (s, 2H), 3.83 (s, 3H). MS: m/z 405.0 (M+H⁺).

Example 112: Synthesis ofN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

Step 1, 2: To a solution of 4-nitro-benzoic acid (836 mg, 5.0 mmol) in(COCl)₂ (5 mL) was added a drop of dry DMF. The reaction was stirred atroom temperature for 1 hour. Then the mixture was concentrated in vacuumto give 4-nitro-benzoyl chloride as a yellow solid, which was dissolvedin dry DCM (40 mL). Then 4-amino-benzonitrile (1.184 g, 10.0 mmol) wasadded into the mixture, followed by TEA (1.518 g, 15.0 mmol). Theresulting mixture was stirred at room temperature for another 1 hour.The reaction was monitored by TLC. Then the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column (DCMas eluent) to afford N-(4-cyanophenyl)-4-nitrobenzamide (726 mg, yield:55%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.94 (brs, 1H),8.39 (dd, J=7.2, 2.0 Hz, 2H), 8.19 (dd, J=7.2, 2.0 Hz, 2H), 7.99 (d,J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H).

Step 3: To a solution of N-(4-cyanophenyl)-4-nitrobenzamide (726 mg,2.72 mmol) in EtOH/H₂O (v/v=40 mL/10 mL) was added powder iron (760 mg,13.58 mmol) and NH₄Cl (727 mg, 13.58 mmol). The resulting mixture wasstirred at 80° C. overnight. The reaction was monitored by LC-MS. Thenpowder iron was filtered off. The filtrate was concentrated in vacuum toafford 4-amino-N-(4-cyano-phenyl)-benzamide (588 mg, yield: 91%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.14 (brs, 1H), 7.96 (d,J=8.8 Hz, 2H), 7.81-7.69 (m, 4H), 6.61 (d, J=8.8 Hz, 2H), 5.86 (s, 2H).

Step 4: To a solution of 4-amino-N-(4-cyano-phenyl)-benzamide (588 mg,2.48 mmol) in DCM (20 mL) was added phenyl carbonchloridate (776 mg,4.96 mmol), followed by TEA (753 mg, 7.44 mmol). The resulting mixturewas stirred at room temperature for 1 hour. The reaction was monitoredby TLC. Then the mixture was concentrated in vacuum to give a residue,which was purified by a silica gel column eluting with DCM to affordphenyl (4-((4-cyanophenyl)carbamoyl)phenyl)carbamate (496 mg, yield:56%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.59 (brs, 1H),10.51 (brs, 1H), 8.02-7.93 (m, 4H), 7.81 (d, J=8.8 Hz, 2H), 767 (d,J=9.2 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.32-7.23 (m, 3H).

Step 5: To a solution of phenyl(4-((4-cyanophenyl)carbamoyl)phenyl)carbamate (150 mg, 0.42 mmol) in ACN(20 mL) was added c-pyridin-4-yl-methylamine (54 mg, 0.50 mmol),followed by TEA (127 mg, 1.26 mmol). The resulting mixture was stirredat 80° C. for 3 hours. The reaction was monitored by LC-MS. Then themixture was concentrated in vacuum to give a residue, which was purifiedby a prep-HPLC with NH₄OH as additive to affordN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide (66.6 mg,yield: 43%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.42 (brs,1H), 9.13 (s, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H), 7.98 (dd, J=7.2, 2.0Hz, 2H), 7.90 (d, J=8.8 Hz, 2H), 7.80 (dd, J=7.2, 2.0 Hz, 2H), 7.57 (d,J=8.8 Hz, 2H), 7.30 (d, J=5.6 Hz, 2H), 6.90 (t, J=6.0 Hz, 1H), 4.35 (d,J=6.0 Hz, 2H). MS: m/z 372.1 (M+H⁺).

Example 113: Synthesis ofN-(3,4-dimethylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.87-7.84 (m, 2H), 7.54-7.52 (m, 2H),7.41-7.35 (m, 4H), 7.10-7.08 (m, 1H), 4.47 (s, 2H), 2.26-2.24 (s, 6H).MS: m/z 375.0 (M+H⁺).

Example 114: Synthesis ofN-(3,4-dimethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD3OD): δ=8.48-8.46 (m, 2H), 7.87-7.85 (m, 2H), 7.55-7.53 (m, 2H),7.41-7.40 (m, 3H), 7.10-7.08 (m, 1H), 6.94-6.92 (m, 1H), 4.47 (s, 2H),2.26-2.24 (s, 6H). MS: m/z 407.0 (M+H⁺).

Example 115: Synthesis ofN-(benzo[d][1,3]dioxol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD3OD): δ=8.48-8.46 (m, 2H), 7.85-7.83 (m, 2H), 7.54-7.52 (m, 2H),7.41-7.39 (m, 2H), 7.28 (m, 1H), 7.04-7.02 (m, 1H), 6.80-6.78 (m, 1H),5.94 (s, 2H), 4.47 (s, 2H). MS: m/z 391.0 (M+H⁺).

Example 116: Synthesis ofN-(4-methoxy-3-methylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD3OD): δ=8.48-8.46 (m, 2H), 7.86-7.84 (m, 2H), 7.54-7.51 (m, 2H),7.41-7.36 (m, 4H), 6.88-6.86 (m, 1H), 4.46 (s, 2H), 3.81 (s, 3H), 2.19(s, 3H). MS: m/z 391.0 (M+H⁺).

Example 117: Synthesis ofN-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, DMSO-d₆): δ=9.87 (s, 1H), 9.10 (s, 1H), 8.51-8.50 (m, 2H),7.86-7.83 (m, 2H), 7.54-7.52 (m, 2H), 7.37 (m, 1H), 7.30-7.29 (m, 2H),7.19-7.16 (m, 1H), 6.92-6.89 (m, 1H), 6.89-6.79 (m, 1H), 4.35-4.34 (s,2H), 4.22-4.21 (m, 4H). MS: m/z 405.0 (M+H⁺).

Example 118: Synthesis ofN-(pyridin-2-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD₃OD): δ=8.48-8.47 (s, 2H), 8.34-8.33 (m, 1H), 8.20-8.18 (m, 1H),7.93-7.91 (m, 2H), 7.84-7.80 (m, 1H), 7.58-7.55 (m, 2H), 7.41-7.40 (m,2H), 7.14-7.13 (m, 1H), 4.47 (s, 2H). MS: m/z 348.0 (M+H⁺).

Example 119: Synthesis ofN-(pyridin-3-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepared as described in exampleN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide. ¹H NMR (400MHz, CD₃OD): δ=8.78-8.77 (s, 1H), 8.38-8.37 (m, 2H), 8.19-8.13 (m, 2H),7.82-7.80 (m, 2H), 7.48-7.46 (m, 2H), 7.34-7.30 (m, 3H), 4.38 (s, 2H).MS: m/z 347.9 (M+H⁺).

Example 120: Synthesis of4-(3-(pyridin-4-ylmethyl)ureido)-N-(pyrimidin-5-yl)benzamide

To a stirred mixture of 4-(3-(pyridin-4-ylmethyl)ureido)benzoic acid (50mg, 0.18 mmol), pyrimidin-5-ylamine (21 mg, 0.22 mmol) and DIEA (71 mg,0.55 mmol) in DMF (5 mL) was added HATU (105 mg, 0.28 mmol). The mixturewas stirred at 40° C. for 3 days. The mixture was diluted with water (20mL), and the aqueous phase was extracted with EtOAc (30 mL*3). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated to dryness in vacuum and theresidue was purified by preparative TLC (DCM/MeOH=10/1) to afford4-(3-(pyridin-4-ylmethyl)ureido)-N-(pyrimidin-5-yl)benzamide (4 mg,yield: 6%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=9.19 (s, 2H),8.89 (s, 1H), 8.48 (d, J=5.2 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 7.58 (d,J=8.4 Hz, 2H), 7.41 (d, J=5.6 Hz, 2H), 4.48 (s, 2H). MS: m/z 349.1(M+H⁺).

Example 121: Synthesis ofN-(3-methylisoxazol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide

The title compound was prepare as described in example4-(3-(pyridin-4-ylmethyl)ureido)-N-(pyrimidin-5-yl)benzamide. ¹H NMR(300 MHz, DMSO-d₆): δ=11.68 (s, 1H), 9.22 (s, 1H), 8.51 (d, J=4.8 Hz,2H), 7.93 (d, J=7.8 Hz, 2H), 7.55 (d, J=7.8 Hz, 2H), 7.30 (d, J=4.5 Hz,2H), 6.98-6.95 (m, 1H), 6.28 (s, 1H), 4.34 (d, J=5.4 Hz, 2H), 2.20 (s,3H). MS: m/z 352.1 (M+H⁺).

Example 122: Synthesis of4-(3-(Pyridin-4-ylmethyl)ureido)-N-(thiophen-2-yl)benzamide

Step 1: To a solution of 4-nitrobenzoic acid (400 mg, 2.39 mmol) in DCM(50 mL) was added oxalyl chloride (395 mg, 3.11 mmol) and DMF (1 drop).The mixture was stirred at room temperature for 1 hr. The solution wasconcentrated to afford the intermediate acyl chloride. It was thendropped to a suspension of thiophen-2-yl-carbamic acid tert-butyl ester(523 mg, 2.63 mmol) and NaH (143 mg, 3.59 mmol) in anhydrous THF (30 mL)and the mixture was stirred at room temperature overnight. Resultant wasquenched with MeOH (3 mL), concentrated and purified by combi-flash (EAin PE: 0 to 30%) to afford tert-butyl(4-nitrobenzoyl)(thiophen-2-yl)carbamate (410 mg, yield: 49%) as a whitesolid.

Step 2: To a solution of (4-nitro-benzoyl)-thiophen-2-yl-carbamic acidtert-butyl ester (410 mg, 1.18 mmol) in DCM (50 mL) was added TFA (2mL). The mixture was stirred at room temperature for 2 hrs. The reactantwas concentrated and diluted with EA (50 mL). The mixture was washedwith aq. K₂CO₃ and the organic layer was dried over Na₂SO₄. The solutionwas concentrated to afford 4-nitro-N-(thiophen-2-yl)benzamide (400 mg,crude) without further purification.

Step 3: To a solution of 4-nitro-N-(thiophen-2-yl)benzamide (400 mg,1.16 mmol) in EtOH (30 mL) was added SnCl₂.2H₂O (2.1 g, 8.1 mmol), itwas then heated at reflux for 2 hrs. After cooled to room temperature,the reaction was quenched by NH₃.H₂O (2 mL). The white precipitate wasfiltrated through celite. The filtrate was concentrated and purified bycombi-flash (EA in PE: 0 to 50%) to afford4-amino-N-(thiophen-2-yl)benzamide (170 mg, yield: 48%) as a whitesolid. MS: m/z 219.1 (M+H⁺).

Step 4: To a solution of 4-amino-N-(thiophen-2-yl)benzamide (170 mg,0.78 mmol) in DCM (20 mL) was added phenyl chloroformate (140 mg, 0.47mmol) and DIEA (0.5 mL), it was stirred at room temperature over 30 minbefore the addition of pyridin-4-ylmethanamine (101 mg, 0.94 mmol). Themixture was then stirred at room temperature overnight. Resultant wasconcentrated and the residue was purified by prep-HPLC to afford4-(3-(pyridin-4-ylmethyl)ureido)-N-(thiophen-2-yl)benzamide (82 mg,yield: 27%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=11.33 (s,1H), 9.14 (s, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.56(d, J=8.4 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 6.97-6.89 (m, 4H), 4.35 (d,J=5.6 Hz, 2H). MS: m/z 353.1 (M+H⁺).

Example 123: Synthesis of Ethyl 4-(3-(oxazol-4-ylmethyl)ureido)benzoate

Step 1: To a solution of ethyl oxazole-4-carboxylate (1.0 g, 7.1 mmol)in THF (20 mL) was added LAH (330 mg, 8.5 mmol) portion wise at 0° C.After stirring at 0° C. for 30 min, H₂O (0.3 mL), 15% NaOH (0.3 mL) andH₂O (0.9 mL) were then added dropwise at 0° C. The mixture was stirredat room temperature for another 20 min, dried over MgSO₄ and filtered.The filtrate was concentrated to give oxazol-4-ylmethanol (390 mg,yield: 56%) as yellow oil. ¹H NMR (300 MHz, CDCl₃): δ=7.90 (s, 1H), 7.64(d, J=0.3 Hz, 1H), 4.63 (s, 2H).

Step 2: To a solution of oxazol-4-ylmethanol (375 mg, 3.8 mmol) and Et₃N(0.8 mL, 5.7 mmol) in DCM (10 mL) was added MsCl (520 mg, 4.5 mmol)dropwise at 0° C. After stirring at room temperature for 20 min, thereaction mixture was diluted with DCM (50 mL) and washed with water (30mL). The DCM solution was dried over Na₂SO₄ and concentrated. Theresidue was dissolved in DMF (20 mL) and NaN₃ (320 mg, 4.9 mmol) wasadded. After stirring at 80° C. for 16 hrs, the reaction mixture waspoured to water (60 mL) and extracted with EA (50 mL×3). The combinedorganic layer was washed with brine (40 mL×3), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column (PE/EA=10/1)to give 4-(azidomethyl)oxazole (180 mg, yield: 38%) as colorless oil. ¹HNMR (400 MHz, CDCl₃): δ=7.91 (s, 1H), 7.68 (d, J=1.2 Hz, 1H), 4.32 (s,2H).

Step 3: To a solution of 4-azidomethyl-oxazole (140 mg, 1.1 mmol) inTHF/H₂O (4 mL/0.5 mL) was added PPh₃ (440 mg, 1.7 mmol). After stirringat room temperature for 16 hrs, the reaction mixture was poured toaq.HCl (2 N, 5 mL) and extracted with DCM (20 mL*2). The acidic layerwas concentrated and co-evaporated with toluene (10 mL*2) to giveoxazol-4-ylmethanamine.HCl (crude) as a white solid.

Step 4: A mixture of C-oxazol-4-yl-methylamine.HCl (crude),4-phenoxycarbonylamino-benzoic acid ethyl ester (320 mg, 1.1 mmol) andDMAP (280 mg, 2.3 mmol) in MeCN (6 mL) was stirred at 80° C. for 10 minand then concentrated. The residue was diluted by DCM (40 mL), washed byaq.HCl (1 N, 20 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by Prep-HPLC (NH₄HCO₃) to give ethyl4-(3-(oxazol-4-ylmethyl)ureido)benzoate (90 mg, yield: 28%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.99 (s, 1H), 8.34 (s, 1H), 7.96 (d,J=0.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.66 (t,J=5.6 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.22 (d, J=5.2 Hz, 2H), 1.30 (t,J=7.2 Hz, 3H). MS: m/z 290.0 (M+H⁺).

Example 124: Synthesis of Ethyl4-(3-((3,5-dimethylisoxazol-4-yl)methyl)ureido)benzoate

Step 1: To a solution of 4-chloromethyl-3,5-dimethyl-isoxazole (1.0 g,6.9 mmol) in dioxane (10 mL) was added NH₃.H₂O (10 mL). After stirringat room temperature for 16 hrs, the reaction mixture was concentratedand washed with MeCN (20 mL) to give(3,5-dimethylisoxazol-4-yl)methanamine (800 mg, yield: 92%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.52 (brs, 2H), 3.81 (s, 2H), 2.45(s, 3H), 2.30 (s, 3H).

Step 2: A mixture of (3,5-dimethylisoxazol-4-yl)methanamine (70 mg, 0.6mmol), 4-phenoxycarbonylamino-benzoic acid ethyl ester (150 mg, 0.5mmol) and TEA (0.2 mL, 1.6 mmol) in MeCN (8 mL) was stirred at 80° C.for 1 h and then concentrated. The residue was diluted with DCM (40 mL),washed with aq.HCl (1 N, 20 mL) and Sat.NaHCO₃ (20 mL). The DCM solutionwas dried over Na₂SO₄, concentrated and purified by Prep-HPLC (NH₃.H₂O)to give ethyl 4-(3-((3,5-dimethylisoxazol-4-yl)methyl)ureido)benzoate(50 mg, yield: 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.85(s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 6.64 (t, J=5.6Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.06 (d, J=5.6 Hz, 2H), 2.38 (s, 3H),2.21 (s, 3H), 1.29 (t, J=7.2 Hz, 3H). MS: m/z 318.0 (M+H⁺).

Example 125: Synthesis of Ethyl4-(3-((1-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate

Step 1: The solution of ethyl 1H-pyrazole-4-carboxylate (2.5 g, 17.9mmol), and iodomethane (3.1 g, 21.5 mmol) in DMF (10 mL) was added K₂CO₃(5.0 g, 35.8 mmol) and then the reaction mixture was stirred at roomtemperature for 16 hrs. Water (50 mL) was added to the mixture and thenextracted by EA (50 mL×2). The organic layer was washed with brine (40mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column (PE/EA=8/1) to give the ethyl1-methyl-1H-pyrazole-4-carboxylate (214 mg, yield: 85%) as a colorlessoil. ¹H NMR (300 MHz, DMSO-d₆): δ=8.28 (s, 1H), 7.82 (s, 1H), 4.26 (q,J=6.9 Hz, 2H), 3.87 (s, 3H), 1.25 (t, J=6.9 Hz, 3H). MS: m/z 155.3(M+H⁺).

Step 2: The solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (0.52g, 3.4 mmol) in EtOH (10 mL) was added NH₄OH (20 mL) and the reactionmixture was stirred at 80° C. for 16 hrs. Then the reaction mixture wasconcentrated under reduced pressure to give the1-methyl-1H-pyrazole-4-carboxamide (0.61 g, yield: quantitative) as acolorless oil. MS: m/z 127.3 (M+H⁺).

Step 3: The solution of 1-methyl-1H-pyrazole-4-carboxamide (0.61 g, 3.4mmol) in THF (10 mL) was added LAH (0.40 g, 10.2 mmol) and the mixturewas stirred at 70° C. for 2 hrs. H₂O (0.5 mL), 15% NaOH (0.5 mL) and H₂O(1.5 mL) were then added dropwise at 0° C. The mixture was stirred atroom temperature for another 20 min, dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give theC-(1-methyl-1H-pyrazol-4-yl)-methylamine (0.58 g, yield: quantitative)as colorless oil.

Step 4: This step was similar to the procedure of ethyl4-(3-((3,5-dimethylisoxazol-4-yl)methyl)ureido)benzoate. ¹H NMR (400MHz, DMSO-d₆): δ=8.86 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.59 (s, 1H),7.51 (d, J=8.0 Hz, 2H), 7.34 (s, 1H), 6.51 (s, 1H), 4.26 (q, J=6.8 Hz,2H), 4.11 (d, J=4.8 Hz, 2H), 3.78 (s, 3H), 1.29 (t, J=6.8 Hz, 3H). MS:m/z 303.0 (M+H⁺).

Example 126: Synthesis ofN-(3-Chloro-phenyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzamide

Step 1: To a solution of 4-nitro-benzoic acid (2.1 g, 12.6 mmol) in DCM(20 mL) was added (COCl)₂ (8.0 g, 62.9 mmol) at 0° C. then one drop ofDMF was added. The reaction mixture was stirred for 1 hr at roomtemperature. The white solid was got by filtration and washed by DCM (10mL) to get the 4-nitro-benzoyl chloride (3.0 g, yield: quantitative) asa white solid.

Step 2: The solution of 4-nitro-benzoyl chloride (3.0 g, 12.6 mmol) andTEA (2.5 g, 25.2 mmol) in DCM (10 mL) was added 3-chloro-phenylamine(1.6 g, 12.6 mmol) and the reaction mixture was stirred at roomtemperature for 2 hrs. The reaction was concentrated under reducedpressure and the residue was purified by silica gel column (PE/EA=5/1)to give the N-(3-chloro-phenyl)-4-nitro-benzamide (1.8 g, yield: 51%) asa yellow solid.

Step 3: To a solution of N-(3-chloro-phenyl)-4-nitro-benzamide (1.8 g,6.5 mmol) and Fe (3.6 g, 65.0 mmol) in MeOH (10 mL) was added a solutionof NH₄Cl (7.0 g, 130.0 mmol) in water (10 mL). The reaction was stirredat 80° C. for 4 hrs. Then the reaction mixture was filtered. Thefiltrate was added to water (10 ml) and then extracted by EA (20 mL×2).The organic layer was washed with brine (40 mL), dried over Na₂SO₄, andconcentrated under reduced pressure to give the4-amino-N-(3-chloro-phenyl)-benzamide (0.9 g, yield: 56%) as a yellowsolid. MS: m/z 247.4 (M+H⁺)

Step 4: The solution of 4-amino-N-(3-chloro-phenyl)-benzamide (501 mg,2.0 mmol) and TEA (404 mg, 4.0 mmol) in DCM (20 mL) was degassed andpurged with N₂. The mixture was stirred at 0° C. for a while. Thenphenyl chroloformate (376 mg, 2.4 mmol) was added and the mixture wasstirred at room temperature for 1 hr. After that, the solution wasconcentrated under reduced pressure. The residue was washed by PE/EA=2/1(10 mL) to give the [4-(3-chloro-phenylcarbamoyl)-phenyl]-carbamic acidphenyl ester (130 mg, yield: 18%) as a white solid.

Step 5: To a solution of [4-(3-chloro-phenylcarbamoyl)-phenyl]-carbamicacid phenyl ester (130 mg, 0.35 mmol) and TEA (71 mg, 0.70 mmol) in MeCN(20 mL) was added C-(1H-pyrazol-4-yl)-methylamine (34 mg, 0.35 mmol).The mixture was refluxed at 80° C. for overnight. After that, thesolution was concentrated under reduced pressure. The residue waspurified by prep-HPLC to giveN-(3-chloro-phenyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzamide (35mg, yield: 27%) as a white solid. ¹H NMR (300 MHz, DMSO-d6): δ=12.67 (s,1H), 10.17 (s, 1H), 8.79 (s, 1H), 7.96 (s, 1H), 7.88 (d, J=3.0 Hz, 2H),7.71 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 4H), 7.35 (t, J=8.7 Hz, 1H),7.11 (d, J=7.8 Hz, 1H), 6.47 (t, J=3.9 Hz, 1H), 4.17 (d, J=5.7 Hz, 2H).MS: m/z 369.9 (M+H⁺).

Example 127: Synthesis of4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-methoxyphenyl)benzamide

The title compound was prepared as described in example4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-chlorophenyl)benzamide. ¹HNMR (400 MHz, DMSO-d6): δ=12.64 (s, 1H), 9.17 (s, 1H), 8.78 (s, 1H),7.87-7.81 (m, 3H), 7.53-7.51 (m, 4H), 7.17-7.14 (m, 1H), 7.09 (d, J=8.4Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.46 (t, J=6.0 Hz, 1H), 4.17 (d, J=5.2Hz, 2H), 3.32 (s, 3H). MS: m/z 365.9 (M+H⁺).

Example 128: Synthesis of4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-chlorophenyl)benzamide

The title compound was prepared as described in example4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-chlorophenyl)benzamide. ¹HNMR (300 MHz, DMSO-d₆): δ=12.62 (s, 1H), 9.78 (s, 1H), 8.78 (s, 1H),7.91 (d, J=9.3 Hz, 2H), 7.62-7.51 (m, 6H), 7.37 (t, J=9.0 Hz, 1H), 7.26(t, J=9.3 Hz, 1H), 6.47 (t, J=6.9 Hz, 1H), 4.17 (d, J=5.4 Hz, 2H). MS:m/z 369.9 (M+H⁺).

Example 129: Synthesis of4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-methoxyphenyl)benzamide

The title compound was prepared as described in example4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-chlorophenyl)benzamide. ¹HNMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 9.89 (s, 1H), 8.77 (s, 1H),7.85 (d, J=8.4 Hz, 2H), 7.67-7.50 (m, 6H), 6.90 (d, J=8.8 Hz, 2H), 6.47(t, J=4.8 Hz, 1H), 7.08 (d, J=4.8 Hz, 2H), 3.74 (s, 3H). MS: m/z 364.0(M−H⁺).

Example 130: Synthesis of4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-chlorophenyl)benzamide

The title compound was prepared as described in example4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-chlorophenyl)benzamide. ¹HNMR (300 MHz, DMSO-d₆): δ=12.62 (s, 1H), 10.13 (s, 1H), 8.78 (s, 1H),7.87-7.78 (m, 4H), 7.54 (d, J=8.7 Hz, 4H), 7.39 (d, J=8.7 Hz, 2H), 6.47(t, J=6.9 Hz, 1H), 4.16 (d, J=4.8 Hz, 2H). MS: m/z 370.0 (M+H⁺).

Example 131: Synthesis of4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-methoxyphenyl)benzamide

The title compound was prepared as described in example4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-chlorophenyl)benzamide. ¹HNMR (400 MHz, DMSO-d₆): δ=12.61 (s, 1H), 9.98 (s, 1H), 8.86 (s, 1H),7.86 (d, J=8.8 Hz, 2H), 7.53-7.51 (m, 4H), 7.46 (t, J=2.4 Hz, 1H), 7.36(d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 6.67-6.64 (m, 1H), 6.53 (t,J=5.2 Hz, 1H), 4.17 (d, J=4.8 Hz, 2H), 3.75 (s, 3H). MS: m/z 366.0(M+H⁺).

Example 132: Synthesis of Ethyl 4-(3-(oxazol-5-ylmethyl)ureido)benzoate

Step 1: To a solution of C-oxazol-5-yl-methylamine hydrochloride (47.2mg, 0.35 mmol) in dioxane (20 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (100 mg, 0.35 mmol) andTEA (70.9 mg, 0.7 mmol). After stirred at 90° C. overnight, the reactionmixture was concentrated in vacuum. The residue was purified by pre-HPLCto afford ethyl 4-(3-(oxazol-5-ylmethyl)ureido)benzoate (22 mg, 22%) asa white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.18 (s, 1H), 7.94 (d, J=8.8Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.07 (s, 1H), 4.51 (s, 2H), 4.35 (q,J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H). MS: m/z 290.0 (M+H)+.

Example 133: Synthesis of Ethyl4-(3-((3-amino-1H-pyrazol-4-yl)methyl)ureido)benzoate

Step 1: To a solution of 3-amino-1H-pyrazole-4-carbonitrile (300 mg,2.78 mmol) in THF (100 mL) was added LiAlIH₄ (316 mg, 8.34 mmol). Afterstirred at reflux overnight, the reaction mixture was quenched by H₂O (2mL). And the mixture was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuum. The residue was used for next stepwithout further purification.

Step 2: To a solution of 4-aminomethyl-1H-pyrazol-3-ylamine (78.5 mg,0.7 mmol) in dioxane (30 mL) was added 4-phenoxycarbonylamino-benzoicacid ethyl ester (200 mg, 0.7 mmol) and TEA (142 mg, 1.4 mmol). Afterstirred at 90° C. overnight, the reaction mixture was concentrated invacuum. The residue was purified by pre-HPLC to afford ethyl4-(3-((3-amino-1H-pyrazol-4-yl)methyl)ureido)benzoate (28 mg, 13%) as ayellow solid. ¹H NMR (400 MHz, CD₃OD): δ=7.91 (d, J=8.8 Hz, 2H), 7.76(s, 1H), 7.50 (d, J=8.8 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 4.19 (s, 2H),1.37 (t, J=7.2 Hz, 3H). MS: m/z 304.1 (M+H)+.

Example 134: Synthesis of Ethyl4-(3-((1H-imidazol-5-yl)methyl)ureido)benzoate

Step 1: To a solution of C-(3H-imidazol-4-yl)-methylamine hydrochloride(119 mg, 0.7 mmol) in dioxane (30 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (200 mg, 0.7 mmol) andTEA (213 mg, 2.1 mmol). After stirred at 90° C. overnight, the reactionmixture was concentrated in vacuum. The residue was purified by pre-HPLCto afford ethyl 4-(3-((1H-imidazol-5-yl)methyl)ureido)benzoate (35 mg,17%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.81 (d, J=1.2 Hz,1H), 7.92 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.46 (s, 1H), 4.48(s, 2H), 4.33 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). MS: m/z 289.1(M+H)+.

Example 135: Synthesis of Ethyl4-(3-((1-methyl-1H-pyrazol-5-yl)methyl)ureido)benzoate

Step 1: To a solution of 2-methyl-2H-pyrazole-3-carboxylic acid (500 mg,3.97 mmol) in DMF (20 mL) was added NH₄Cl (318 mg, 6.0 mmol), HATU (1.8g, 4.8 mmol), and DIPEA (1.03 g, 8 mmol). After stirred at roomtemperature overnight, the reaction mixture was evaporated in vacuum.The residue was partitioned in a mixture of H₂O (30 mL) and EA (30 mL).Organic phase was collected, dried over anhydrous Na₂SO₄, and evaporatedin vacuum. The residue was used for next step without furtherpurification.

Step 2: To a solution of 2-methyl-2H-pyrazole-3-carboxylic acid amide(crude, 3.97 mmol) in THF (50 mL) was added LiAlH₄ (453 mg, 11.9 mmol).After stirred at reflux overnight, the reaction mixture was quenched byH₂O (2 mL). And the mixture was then dried over anhydrous Na₂SO₄ andfiltered. The filtrate was evaporated in vacuum. The residue was usedfor next step without further purification.

Step 3: To a solution of C-(2-methyl-2H-pyrazol-3-yl)-methylamine (78mg, 0.7 mmol) in dioxane (30 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (200 mg, 0.7 mmol) andTEA (213 mg, 2.1 mmol). After stirred at 90° C. overnight, the reactionmixture was concentrated in vacuum. The residue was purified by pre-HPLCto afford ethyl 4-(3-((1-methyl-1H-pyrazol-5-yl)methyl)ureido)benzoate(45 mg, 21%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=7.91 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=1.6 Hz, 1H), 6.24 (d, J=1.6Hz, 1H), 4.47 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.87 (s, 3H), 1.37 (t,J=7.2 Hz, 3H). MS: m/z 303.0 (M+H)+.

Example 136: Synthesis of Ethyl4-(3-((1H-imidazol-4-yl)methyl)ureido)benzoate

Step 1: To a solution of 1H-imidazole-4-carbonitrile (300 mg, 3.2 mmol)in THF (50 mL) was added LiAlH₄ (365 mg, 9.6 mmol). After stirred atreflux overnight, the reaction mixture was quenched by H₂O (2 mL). Andthe mixture was dried over anhydrous Na₂SO₄ and filtered. The filtratewas evaporated in vacuum. The residue was used for next step withoutfurther purification.

Step 2: To a solution of C-(1H-imidazol-4-yl)-methylamine (81.6 mg, 0.84mmol) in dioxane (30 mL) was added 4-phenoxycarbonylamino-benzoic acidethyl ester (200 mg, 0.7 mmol) and TEA (213 mg, 2.1 mmol). After stirredat 90° C. overnight, the reaction mixture was concentrated in vacuum.The residue was purified by pre-HPLC to afford ethyl4-(3-((1H-imidazol-4-yl)methyl)ureido)benzoate (30 mg, 15%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=11.93 (s, 1H), 8.98 (s, 1H), 7.83(d, J=8.8 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 6.95 (s, 1H),6.51 (t, J=4.8 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 4.19 (d, J=4.8 Hz, 2H),1.29 (t, J=7.2 Hz, 3H). MS: m/z 289.0 (M+H)⁺.

Example 137: Synthesis of Ethyl4-(3-((1H-pyrazol-3-Yl)methyl)ureido)benzoate

Step 1: To a solution of C-(1H-pyrazol-3-yl)-methylamine (81.5 mg, 0.84mmol) in dioxane (30 mL) was added 4-phenoxycarbonylamino-benzoic acidethyl ester (200 mg, 0.7 mmol) and DIPEA (181 mg, 1.4 mmol). Afterstirred at 90° C. overnight, the reaction mixture was concentrated invacuum. The residue was purified by pre-HPLC to afford ethyl4-(3-((1H-pyrazol-3-yl)methyl)ureido)benzoate (25 mg, 12%) as a whitesolid. ¹H NMR (400 MHz, CD₃OD): δ=7.91 (d, J=8.8 Hz, 2H), 7.57 (s, 1H),7.49 (d, J=8.4 Hz, 2H), 6.29 (s, 1H), 4.43 (s, 2H), 4.32 (q, J=7.2 Hz,2H), 1.37 (t, J=7.2 Hz, 3H). MS: m/z 289.0 (M+H)⁺.

Example 138: Synthesis of Ethyl4-(3-((3-methyl-1H-pyrazol-4-Yl)methyl)ureido)benzoate

Step 1: 3-Methyl-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 3.24mmol) was dissolved in NH₄OH (30 mL). After stirred at 70° C. overnight,the mixture was evaporated in vacuum to afford crude3-methyl-1H-pyrazole-4-carboxylic acid amide as a yellow solid which wasused for next step without further purification.

Step 2: To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid amide(crude, 3.24 mmol) in THF (30 mL) was added LiAlH₄ (492 mg, 13 mmol).After stirred at reflux overnight, the reaction was quenched by H₂O (2mL). Then the mixture was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuum to affordC-(3-methyl-1H-pyrazol-4-yl)-methylamine as a crude product which wasused for next step without further purification.

Step 3: To a solution of C-(3-methyl-1H-pyrazol-4-yl)-methylamine (93.3mg, 0.84 mmol) in dioxane (20 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (200 mg, 0.7 mmol) andDIPEA (181 mg, 1.4 mmol). After stirred at 90° C. overnight, thereaction mixture was concentrated in vacuum. The residue was purified bypre-HPLC to afford ethyl4-(3-((3-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate (27 mg, 13%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=12.3 (s, 1H), 8.84 (s, 1H),7.82 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 6.42 (s,1H), 4.26 (q, J=7.2 Hz, 2H), 4.09 (d, J=4.8 Hz, 2H), 2.18 (s, 3H), 1.29(t, J=7.2 Hz, 3H). MS: m/z 303.0 (M+H)⁺.

Example 139: Synthesis of Ethyl4-(3-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate

Step 1: To a solution of 1-bromomethyl-4-methoxy-benzene (2 g, 10 mmol)in DMF (20 mL) was added NaN₃ (720 mg, 11 mmol) and K₂CO₃ (2.07 g, 15mmol). After stirred at 65° C. overnight, the mixture was evaporated invacuum. The residue was purified by silica gel column chromatograph(PE/EA=5/1) to afford 1-azidomethyl-4-methoxy-benzene (1.6 g, 98%) as acolorless oil.

Step 2: To a solution of 1-azidomethyl-4-methoxy-benzene (1.6 g, 10mmol) in toluene (50 mL) was added prop-2-yn-1-ol (616 mg, 11 mmol) andCuI (95 mg, 0.5 mmol). After stirred at 90° C. overnight, the reactionmixture was filtered. The filtrate was evaporated in vacuum. The residuewas purified by flash column (ACN in water, 10% to 95%) to afford[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol (1.3 g, 70%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.95 (s, 1H), 7.29 (d, J=8.8Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 5.47 (s, 2H), 5.15 (s, 1H), 4.48 (s,2H), 3.73 (s, 3H).

Step 3: To a solution of[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2.64mmol) in a mixture of toluene (9 mL) and DMF (1 mL) was added DPPA (1.45g, 5.28 mmol) and DBU (803 mg, 5.28 mmol). Then the reaction mixture washeated to 50° C. for 36 hrs. Then the mixture was diluted in H₂O (50mL), and extracted by EA (50 mL×3). Organic phase was combined, driedover anhydrous Na₂SO₄, and evaporated in vacuum. The residue waspurified by silica gel column chromatograph (PE:EA=2:1) to afford4-azidomethyl-1-(4-methoxy-benzyl)-1H-[1,2,3]triazole (401 mg, 72%). ¹HNMR (400 MHz, DMSO-d₆): δ=8.16 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 6.92 (d,J=8.8 Hz, 2H), 5.53 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H).

Step 4: To a solution of4-azidomethyl-1-(4-methoxy-benzyl)-1H-[1,2,3]triazole (400 mg, 1.64mmol) in MeOH (20 mL) was added 10% Pd/C (174 mg, 0.16 mmol). Afterstirred at room temperature overnight under balloon hydrogen atmosphere,the reaction mixture was filtered. The filtrate was evaporated in vacuumto afford C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine asa crude product which was used for next step without furtherpurification.

Step 5: To a solution ofC-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine (358 mg,1.64 mmol) in dioxane (20 mL) was added 4-phenoxycarbonylamino-benzoicacid ethyl ester (468 mg, 1.64 mmol) and DIPEA (424 mg, 3.28 mmol).After stirred at 90° C. overnight, the reaction mixture was concentratedin vacuum. The residue was purified by silica gel column chromatograph(DCM/MeOH=10/1) to afford ethyl4-(3-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate(350 mg, 52%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.99 (s,1H), 7.96 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.29(d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 5.48 (s, 2H),4.32 (d, J=5.2 Hz, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.73 (s, 3H), 1.29 (t,J=7.2 Hz, 3H). MS: m/z 410.0 (M+H)⁺.

Example 140: Synthesis of Ethyl4-(3-((1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate

Ethyl4-(3-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate(100 mg, 0.24 mmol) was dissolved in TFA (20 mL) and heated to refluxovernight. Then the solvent was removed in vacuum. The residue waspurified by pre-HPLC to afford ethyl4-(3-((1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate (42 mg, 60%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=15.01 (s, 0.35H), 14.71 (s,0.65H), 9.01 (s, 1H), 7.95 (s, 0.35H), 7.83 (d, J=8.8 Hz, 2H), 7.65 (s,0.65H), 7.52 (d, J=8.8 Hz, 2H), 6.74 (t, J=4.8 Hz, 1H), 4.38 (d, J=5.6Hz, 2H), 4.26 (q, J=6.8 Hz, 2H), 1.30 (t, J=6.8 Hz, 3H). MS: m/z 290.0(M+H)⁺.

Example 141: Synthesis of Ethyl4-(3-((1-methyl-1H-imidazol-5-yl)methyl)ureido)benzoate

Step 1: To a solution of 3-methyl-3H-imidazole-4-carboxylic acid (200mg, 1.58 mmol) in DCM (10 mL) was added (COCl)₂ (400 mg, 3.16 mmol) andDMF (2 drops). After stirred at room temperature overnight, the reactionmixture was evaporated in vacuum. The residue was then dissloved in 7 NNH₃ in MeOH (10 mL). After stirred at room temperature overnight, thereaction mixture was evaporated in vacuum to afford3-methyl-3H-imidazole-4-carboxylic acid amide as a crude product whichwas used for next step without further purification.

Step 2: To a solution of 3-methyl-3H-imidazole-4-carboxylic acid amide(188 mg, 1.5 mmol) in THF (20 mL) was added LiAlH₄ (228 mg, 6 mmol).After stirred at reflux overnight, the reaction was quenched by H₂O (2mL). Then the mixture was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuum to affordC-(3-methyl-3H-imidazol-4-yl)-methylamine as a crude product which wasused for next step without further purification.

Step 3: To a solution of C-(3-methyl-3H-imidazol-4-yl)-methylamine (89mg, 0.80 mmol) in dioxane (10 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (150 mg, 0.53 mmol) andDIPEA (137 mg, 1.06 mmol). After stirred at 90° C. overnight, thereaction mixture was concentrated in vacuum. The residue was purified bypre-HPLC to afford ethyl4-(3-((1-methyl-1H-imidazol-5-yl)methyl)ureido)benzoate (20 mg, 13%) asa white solid. ¹H NMR (400 MHz, CD₃OD): δ=7.91 (d, J=8.4 Hz, 2H), 7.64(s, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.95 (s, 1H), 4.44 (s, 2H), 4.32 (q,J=7.2 Hz, 2H), 3.71 (s, 3H), 1.37 (t, J=7.2 Hz, 3H). MS: m/z 303.0(M+H)⁺.

Example 142: Synthesis of Ethyl4-(3-((1-methyl-1H-imidazol-4-yl)methyl)ureido)benzoate

Step 1: To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (1 g,7.94 mmol) in DCM (10 mL) was added (COCl)₂ (2 g, 15.9 mmol) and DMF (2drops). After stirred at room temperature for 5 hrs, the reactionmixture was evaporated in vacuum. The residue was then dissloved in 7 NNH₃ in MeOH (10 mL). After stirred at room temperature overnight, thereaction mixture was evaporated in vacuum. The residue was purified byflash column chromatograph (ACN in water, 5% to 60%) to afford1-methyl-1H-imidazole-4-carboxylic acid amide (480 mg, 48%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.62 (d, J=11.6 Hz, 2H), 7.24 (s,1H), 7.03 (s, 1H), 3.68 (s, 3H).

Step 2: To a solution of 1-methyl-1H-imidazole-4-carboxylic acid amide(480 mg, 3.84 mmol) in THF (30 mL) was added LiAlH₄ (584 mg, 15.4 mmol).After stirred at reflux overnight, the reaction was quenched by H₂O (2mL). Then the mixture was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuum to affordC-(1-methyl-1H-imidazol-4-yl)-methylamine as a crude product which wasused for next step without further purification.

Step 3: To a solution of C-(1-methyl-1H-imidazol-4-yl)-methylamine (110mg, 1.06 mmol) in dioxane (5 mL) was added4-phenoxycarbonylamino-benzoic acid ethyl ester (150 mg, 0.53 mmol) andDIPEA (137 mg, 1.06 mmol). After stirred at 90° C. overnight, thereaction mixture was concentrated in vacuum. The residue was purified bypre-HPLC to afford ethyl4-(3-((1-methyl-1H-imidazol-4-yl)methyl)ureido)benzoate (45 mg, 28%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.96 (s, 1H), 7.82 (d,J=7.2 Hz, 2H), 7.51-7.49 (m, 3H), 6.97 (s, 1H), 6.50 (t, J=6.0 Hz, 1H),4.25 (q, J=7.2 Hz, 2H), 4.13 (d, J=4.8 Hz, 2H), 3.60 (s, 3H), 1.37 (t,J=7.2 Hz, 3H). MS: m/z 303.0 (M+H)⁺.

Example 143: Synthesis ofN-Cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of 4-amino-benzenesulfonic acid (346.4 mg, 2.00mmol) in THF (30 mL) was added phenyl chloroformate (376 mg, 2.40 mmol)and followed by NaHCO₃ (504 mg, 6.00 mmol). The resulting mixture wasstirred at room temperature overnight. The reaction was monitored byLC-MS. Then THF was removed in vacuum to give a residue which was mixedwith H₂O (20 mL) and acidified to adjust pH=1-2 with conc.HCl. Theprecipitate formed from the mixture was filtered. The cake was washedwith H₂O (20 mL*3) and air-dried to afford4-phenoxycarbonylamino-benzenesulfonic acid (524 mg, yield: 89%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.33 (brs, 1H), 7.56 (d,J=8.4 Hz, 2H), 7.49-7.40 (m, 4H), 7.30-7.21 (m, 3H).

Step 2: To a stirring suspension of4-phenoxycarbonylamino-benzenesulfonic acid (524 mg, 1.78 mmol) indioxane (30 mL) was added c-pyridin-4-yl-methylamine (232 mg, 2.14 mmol)and followed by TEA (542 mg, 5.36 mmol). The resulting mixture wasstirred at 80° C. overnight. The reaction was monitored by LC-MS. Thenthe mixture was concentrated in vacuum to give a residue which was mixedwith H₂O (20 mL) and acidified to adjust pH=5-6 with conc.HCl. Theprecipitate formed from the mixture was filtered. The cake was washedwith H₂O (20 mL*3) and air-dried to afford4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonic acid (526 mg, yield:96%) as a white solid.

Step 3, 4: To a solution of4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonic acid (70 mg, 0.228 mmol)in (COCl)₂ (4 mL) was added a drop of dry DMF. The reaction was stirredat room temperature for 1 hour. Then the mixture was concentrated invacuum to give 4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonyl chlorideas a yellow solid which was dissolved in dry DCM (20 mL). Thencyclohexylamine (27.2 mg, 0.273 mmol) was added into the mixture andfollowed by TEA (69.2 mg, 0.684 mmol). The resulting mixture was stirredat room temperature for another 1 hour. The reaction was monitored byLC-MS. Then the mixture was concentrated in vacuum to give a residuewhich was purified by a reverse-phase column (5-95% ACN in H₂O) toafford N-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(82.7 mg, yield: 93%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.23 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H),7.57 (d, J=8.8 Hz, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.29 (d, J=6.0 Hz, 2H),6.97 (t, J=5.6 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 2.92-2.79 (m, 1H),1.65-1.49 (m, 4H), 1.47-1.38 (m, 1H), 1.17-0.95 (m, 5H). MS: m/z 389.1(M+H⁺).

Example 144: Synthesis ofN-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.15 (brs, 1H), 8.52-8.50 (d, J=1.2 Hz, 2H), 7.67(d, J=7.2 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.18(s, 2H), 6.89 (brs, 1H), 4.34 (d, J=6.0 Hz, 2H). MS:m/z 307.0 (M+H⁺)

Example 145: Synthesis ofN-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48 (d, J=6.0 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.61(d, J=8.8 Hz, 2H), 7.41 (d, J=5.6 Hz, 2H), 4.47 (s, 2H), 2.49 (s, 3H).MS:m/z 320.9 (M+H⁺).

Example 146: Synthesis ofN-Propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.65 (d,J=8.8 Hz, 2H), 7.60 (d, J=9.2 Hz, 2H), 7.38 (t, J=6.0 Hz, 1H), 7.30 (d,J=6.0 Hz, 2H), 6.94 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.71-2.60(m, 2H), 1.42-1.30 (m, 2H), 0.79 (t, J=7.2 Hz, 3H). MS: m/z 349.0(M+H⁺).

Example 147: Synthesis ofN-Isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.24 (brs, 1H), 8.51 (s, 2H), 7.61 (d, J=28.8 Hz,4H), 7.37 (brs, 1H), 7.30 (s, 2H), 6.91 (brs, 1H), 4.34 (s, 2H), 3.16(s, 1H). 0.92 (s, 6H). MS:m/z 349.0 (M+H⁺)

Example 148: Synthesis ofN-Cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.22 (brs, 1H), 8.52-8.50 (dd, J=1.6 Hz, 2H), 7.69(brs, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.60 (d, J=9.2 Hz, 2H), 7.30 (d,J=6.0 Hz, 2H), 6.95-6.92 (brs, 1H), 4.35 (d, J=6.0 Hz, 2H). 2.07-2.05(m, 1H), 0.48-0.43 (m, 2H), 0.36-0.32 (m, 2H). MS:m/z 346.9 (M+H⁺)

Example 149: Synthesis ofN-Cyclobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48 (d, J=6.0 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.58(d, J=8.8 Hz, 2H), 7.40 (d, J=5.2 Hz, 2H), 4.47 (s, 2H), 3.71-3.67 (m,1H), 2.03-1.96 (m, 2H), 1.83-1.71 (m, 2H), 1.61-1.50 (m, 2H). MS:m/z361.0 (M+H⁺).

Example 150: Synthesis ofN-cyclopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.23 (brs, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.65 (d,J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.43 (d, J=6.8 Hz, 1H), 7.30 (d,J=5.6 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.36-3.28(m, 1H), 1.63-1.46 (m, 4H), 1.42-1.32 (m, 2H), 1.31-1.18 (m, 2H). MS:m/z 375.0 (M+H⁺).

Example 151: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrrolidin-3-yl-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.41 (brs, 1H), 8.49 (dd, J=4.4, 1.6 Hz, 2H),7.70-7.56 (m, 4H), 7.29 (d, J=5.6 Hz, 2H), 7.14 (t, J=5.6 Hz, 1H), 4.33(d, J=5.6 Hz, 2H), 3.50-3.42 (m, 1H), 2.81-2.60 (m, 3H), 2.46-2.38 (m,1H), 1.74-1.61 (m, 1H), 1.44-1.34 (m, 1H). MS: m/z 376.0 (M+H⁺).

Example 152: Synthesis ofN-(1-Methyl-pyrrolidin-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.24 (brs, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.70-7.62(m, 3H), 7.58 (d, J=9.2 Hz, 2H), 7.30 (d, J=5.2 Hz, 2H), 6.97 (t, J=5.6Hz, 1H), 4.34 (d, J=5.6 Hz, 2H), 3.61-3.50 (m, 1H), 2.49-2.45 (m, 1H),2.40-2.28 (m, 2H), 2.14 (s, 3H), 2.13-2.09 (m, 1H), 1.90-1.78 (m, 1H),1.47-1.36 (m, 1H). MS: m/z 390.0 (M+H⁺).

Example 153: Synthesis ofN-(tert-butyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.15 (s, 1H), 8.51-8.49 (m, 2H), 7.68-7.65 (m,2H), 7.57-7.54 (m, 2H), 7.30-7.28 (m, 3H), 6.94-6.90 (m, 1H), 4.35-4.33(s, 2H), 1.07 (s, 9H). MS: m/z 363.0 (M+H⁺).

Example 154: Synthesis ofN-(2-Dimethylamino-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): 8.48 (d, J=6.0 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 8.8(d, J=8.8 Hz, 2H), 7.41 (d, J=6.0 Hz, 2H), 4.47 (s, 2H), 3.00-2.97 (t,J=6.4 Hz, 2H), 2.63-2.60 (t, J=6.0 Hz, 2H). 2.37 (s, 6H). MS:m/z 378.0(M+H⁺)

Example 155: Synthesis ofN-Cyclopropylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.18 (brs, 1H), 8.52 (d, J=4.4 Hz, 2H), 7.65 (d,J=8.4 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.52 (brs, 1H), 7.31 (d, J=5.2Hz, 2H), 6.93 (brs, 1H), 4.35 (t, J=6.0 Hz, 2H), 2.61 (t, J=6.4 Hz, 2H).0.79-0.76 (t, J=7.6 Hz, 1H), 0.36-0.32 (m, 2H), 0.07-0.04 (in, 2H).MS:m/z 361.0 (M+H⁺)

Example 156: Synthesis ofN-Cyclobutylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepare as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.20 (brs, 1H), 8.52 (d, J=4.8 Hz, 2H), 7.65-7.57(m, 4H), 7.39 (brs, 1H), 7.31 (d, J=5.2 Hz, 2H), 6.95 (brs, 1H), 4.35(d, J=6.0 Hz, 2H), 2.71-2.68 (t, J=6.4 Hz, 2H). 2.32.28 (m, 1H),1.90-1.86 (m, 2H), 1.77-1.71 (m, 2H), 1.58-1.54 (m, 2H). MS:m/z 375.0(M+H⁺)

Example 157: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-pyrrolidin-1-yl-ethyl)-benzensulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.51 (d, J=4.8 Hz, 2H), 7.67-7.58(dd, J=8.4 Hz, 4H), 7.30 (d, J=4.8 Hz, 3H), 7.00-6.97 (brs, 1H), 4.35(d, J=5.6, 2H), 2.82-2.78 (t, J=6.8 Hz, 2H), 2.45-2.42 (t, J=6.8 Hz,2H), 2.37 (s, 4H). 1.63 (s, 4H). MS:m/z 404.0 (M+H⁺)

Example 158: Synthesis ofN-[2-(4-Methyl-piperazin-1-yl)-ethyl]-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.51-8.50 (d, J=6.0 Hz, 2H),7.66-7.57 (dd, J=8.4 Hz, 4H), 7.30-7.28 (d, J=5.6 Hz, 2H), 6.94 (brs,1H), 4.35-4.33 (d, J=6.0 Hz, 2H), 2.80-2.78 (m, 2H), 2.29-2.26 (t, 9H).2.12 (s, 4H). MS:m/z 433.0 (M+H⁺)

Example 159: Synthesis ofN-(2-Morpholin-4-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.23 (brs, 1H), 8.51 (dd, J=4.4, 1.2 Hz, 2H), 7.66(d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.33 (t, J=5.6 Hz, 1H), 7.29(d, J=5.6 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H),3.56-3.46 (m, 4H), 2.86-2.77 (m, 2H), 2.37-2.19 (m, 6H). MS: m/z 420.2(M+H⁺).

Example 160: Synthesis ofN-(2-Piperidin-1-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.51 (dd, J=4.4, 1.2 Hz, 2H), 7.65(d, J=8.8 Hz, 2H), 7.59 (d, J=9.2 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.25(brs, 1H), 6.94 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 2.83-2.74 (m,2H), 2.30-2.15 (m, 6H), 1.49-1.38 (m, 4H), 1.37-1.28 (m, 2H). MS: m/z418.2 (M+H⁺).

Example 161: Synthesis ofN-(2-Hydroxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.22 (brs, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.65 (d,J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.38 (t, J=6.0 Hz, 1H), 7.30 (d,J=6.0 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.67 (brs, 1H), 4.35 (d, J=5.6Hz, 2H), 3.48-3.28 (m, 2H), 2.81-2.69 (m, 2H). MS: m/z 350.9 (M+H⁺).

Example 162: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(tetrahydro-furan-3-yl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 7.71(d, J=6.4 Hz, 1H), 7.67 (d, J=9.2 Hz, 2H), 7.60 (d, J=9.2 Hz, 2H), 7.29(d, J=6.0 Hz, 2H), 6.96 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H),3.72-3.52 (m, 4H), 3.32-3.39 (m, 1H), 1.91-1.81 (m, 1H), 1.63-1.54 (m,1H). MS: m/z 377.0 (M+H⁺).

Example 163: Synthesis ofN-(2-Methoxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H), 7.65(d, J=8.8 Hz, 2H), 7.58 (d, J=9.2 Hz, 2H), 7.51 (t, J=6.0 Hz, 1H), 7.30(d, J=6.0 Hz, 2H), 6.93 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H),3.31-3.26 (m, 2H), 3.16 (s, 3H), 2.88-2.81 (m, 2H). MS: m/z 365.1(M+H⁺).

Example 164: Synthesis ofN-(3-Methoxy-propyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.51 (d, J=4.8 Hz, 2H), 7.65-7.58(dd, J=8.8 Hz, 4H), 7.39-7.36 (brs, 1H), 7.30 (d, J=4.8 Hz, 2H),6.95-6.92 (brs, 1H), 4.35 (d, J=5.6 Hz, 2H), 3.28-3.24 (t, 2H), 3.15 (s,3H), 2.75-2.70 (dd, J=6.4 Hz, 2H), 1.60-1.53 (m, 2H). MS:m/z 397.0(M+H⁺)

Example 165: Synthesis ofN-(1-Ethyl-pyrrolidin-2-ylmethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.22 (brs, 1H), 8.51-8.50 (dd, J=1.2 Hz, 2H),7.66-7.30 (dd, J=9.2 Hz, 4H), 7.28 (d, J=5.6 Hz, 3H), 6.96-6.93 (brs,1H), 4.34 (d, J=6.0 Hz, 2H), 2.97-2.93 (brs, 1H), 2.76 (d, J=11.6 Hz,1H). 2.57-2.33 (m, 2H), 2.17-2.01 (m, 2H), 1.77-1.61 (m, 1H), 1.75-1.23(m, 4H), 0.96-0.92 (t, J=0.7.2 Hz, 3H). MS:m/z 418.0 (M+H⁺)

Example 166: Synthesis ofN-neopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48 (d, J=4.8 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.57(d, J=8.8 Hz, 2H), 7.41 (d, J=5.6 Hz, 2H), 4.47 (s, 2H), 2.55 (s, 2H),0.87 (s, 9H). MS: m/z 377.0 (M+H)⁺.

Example 167: Synthesis ofN-(1-Cyclobutyl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of 1-cyclobutyl-ethanone (500 mg, 5.1 mmol) in 7 NNH₃ in MeOH (10 mL) was added 10% Pd/C (270 mg, 0.26 mmol). Afterstirred at room temperature under balloon hydrogen atmosphere overnight,the reaction mixture was filtered. The filtrate was evaporated in vacuumto afford 1-cyclobutyl-ethylamine as a crude product which was used fornext step without further purification.

Step 2: To a solution of 4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonicacid (150 mg, 0.49 mmol) in DCM (15 mL) was added (COCl)₂ (124 mg, 0.98mmol) and DMF (2 drops). After stirred at room temperature for 5 hrs,the reaction mixture was evaporated in vacuum. The residue was disslovedin DMF (5 mL), and then 1-cyclobutyl-ethylamine (73 mg, 0.74 mmol) andDIPEA (190 mg, 1.47 mmol) were added. After stirred at room temperatureovernight, the residue was purified by pre-HPLC to affordN-(1-cyclobutyl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(30 mg, 16%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.15 (s,1H), 8.50 (d, J=4.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.8 Hz,2H), 7.29 (d, J=4.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 1H), 6.91 (t, J=4.8 Hz,1H), 4.34 (d, J=5.2 Hz, 2H), 3.01-2.96 (m, 1H), 2.16-2.10 (m, 1H),1.81-1.46 (m, 6H), 0.72 (d, J=6.4 Hz, 3H). MS: m/z 389.0 (M+H)⁺.

Example 168: Synthesis ofN-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.18 (brs, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H), 7.92(t, J=6.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.58 (d, J=9.2 Hz, 2H),7.32-7.26 (m, 4H), 7.26-7.20 (m, 3H), 6.92 (t, J=6.0 Hz, 1H), 4.35 (d,J=6.0 Hz, 2H), 3.92 (d, J=6.4 Hz, 2H). MS: m/z 396.9 (M+H⁺).

Example 169: Synthesis ofN-Benzyl-4-(3-benzyl-ureido)-benzenesulfonamide

The title compound was prepare as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.04 (brs, 1H), 7.91 (t, J=6.4 Hz, 1H), 7.66 (d,J=8.8 Hz, 2H), 7.57 (d, J=9.2 Hz, 2H), 7.38-7.19 (m, 10H), 6.81 (t,J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 3.92 (d, J=6.4 Hz, 2H). MS: m/z395.9 (M+H⁺).

Example 170: Synthesis ofN-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD3OD): δ=8.48-8.47 (m, 2H), 7.70-7.68 (m, 2H), 7.54-7.52 (m,2H), 7.41-7.39 (m, 2H), 7.31-7.20 (m, 2H), 7.07-7.04 (m, 1H), 6.99-6.94(m, 1H), 4.46 (s, 2H), 4.40 (s, 2H). MS: m/z 414.9 (M+H⁺).

Example 171: Synthesis ofN-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD3OD): δ=8.50-8.48 (m, 2H), 7.77-7.71 (m, 2H), 7.58-7.55 (m,2H), 7.42-7.40 (m, 2H), 7.30-7.23 (m, 1H), 7.06-6.91 (m, 3H), 4.48 (s,2H), 4.05 (s, 2H). MS: m/z 414.9 (M+H⁺).

Example 172: Synthesis ofN-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD3OD): δ=7.70-7.68 (m, 2H), 7.55-7.53 (m, 2H), 7.36-733 (m,2H), 7.24-7.20 (m, 2H), 7.07-7.03 (m, 2H), 6.99-6.94 (m, 2H), 4.37 (s,2H), 4.00 (s, 2H). MS: m/z 411.0 (M+H⁺).

Example 173: Synthesis ofN-(2-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.22 (brs, 1H), 8.51 (d, J=5.6 Hz, 2H), 8.04-8.00(brs, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.45-7.43 (t,1H), 7.40-7.38 (t, 1H), 7.33-7.28 (m, 4H), 6.95-6.92 (brs, 1H), 4.35 (d,J=6.0 Hz, 2H), 4.01 (d, J=6.0 Hz, 2H). MS:m/z 430.9 (M+H⁺)

Example 174: Synthesis ofN-(3-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepare as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.28 (brs, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H), 8.00(brs, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.32-7.27 (m,5H), 7.21 (d, J=7.2 Hz, 1H), 6.98 (brs, 1H), 4.35 (d, J=6.0 Hz, 2H),3.96 (d, J=6.4 Hz, 2H). MS:m/z 430.9 (M+H⁺)

Example 175: Synthesis ofN-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48-8.46 (s, 2H), 7.70-7.68 (m, 2H), 7.55-7.53 (m,2H), 7.41-7.39 (m, 2H), 7.24-7.18 (m, 4H), 4.47 (s, 2H), 4.01 (s, 2H).MS: m/z 428.9 (M+H⁺).

Example 176: Synthesis ofN-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48 (m, 2H), 7.66-7.64 (m, 2H), 7.51-7.49 (m, 2H),7.40-7.39 (m, 2H), 7.19-7.15 (m, 2H), 6.83-6.79 (m, 2H), 4.46 (s, 2H),4.04 (s, 2H), 3.71 (s, 3H). MS: m/z 427.0 (M+H⁺).

Example 177: Synthesis ofN-(3-Methoxy-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.51 (d, J=5.7 Hz, 2H), 7.93-7.91(m, 1H), 7.82-7.79 (m, 2H), 7.89-7.56 (m, 4H), 7.29 (d, J=5.7 Hz, 2H),7.22-7.16 (m, 1H), 6.94-6.82 (m, 1H), 6.79-7.76 (m, 3H), 4.34 (d, J=6.0Hz, 2H), 3.91 (d, J=6.0 Hz, 2H), 3.69 (s, 3H). MS: m/z 427.1 (M+H⁺).

Example 178: Synthesis ofN-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepare as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.51 (dd, J=6.0 Hz, 2H), 7.83 (t,J=5.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.29 (d,J=5.6 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 6.96 (t, J=6.8 Hz, 1H), 6.83 (d,J=8.8 Hz, 2H), 4.34 (d, J=6.4 Hz, 2H), 3.85 (d, J=4.8 Hz, 2H), 3.71 (s,3H). MS:m/z 427.0 (M+H⁺).

Example 179: Synthesis ofN-(2-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d6): δ=9.20 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.75-7.58(m, 5H), 7.30 (d, J=5.1 Hz, 2H), 7.20-7.13 (m, 4H), 6.96-6.92 (m, 1H),4.35 (d, J=5.7 Hz, 2H), 3.87 (d, J=6.3 Hz, 2H), 2.20 (s, 3H). MS: m/z411.1 (M+H⁺).

Example 180: Synthesis ofN-(3-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.53 (s, 1H), 8.75 (d, J=6.8 Hz, 2H), 7.89-7.86(m, 1H), 7.74 (d, J=6.4 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.58 (d, J=9.2Hz, 2H), 7.33-7.30 (m, 1H), 7.17-7.14 (m, 1H), 7.03-7.00 (m, 3H), 4.52(d, J=6.0 Hz, 2H), 4.89 (d, J=6.0 Hz, 2H), 2.23 (s, 3H). MS: m/z 411.1(M+H⁺).

Example 181: Synthesis ofN-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.51-8.49 (m, 2H), 7.87-7.82 (m,1H), 7.67-7.62 (m, 2H), 7.59-7.56 (m, 2H), 7.30-7.28 (m, 2H), 7.13-7.06(m, 4H), 6.95-6.91 (m, 1H), 4.37-4.33 (s, 2H), 3.87-3.86 (s, 2H), 2.25(s, 3H). MS: m/z 411.0 (M+H⁺).

Example 182: Synthesis ofN-(2-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.35-9.26 (m, 1H), 8.70 (s, 1H), 8.48 (d, J=4.8Hz, 1H), 7.88-7.85 (m, 2H), 7.72-7.46 (m, 6H), 7.26 (d, J=5.2 Hz, 2H),6.95 (brs, 1H), 5.00-4.88 (m, 2H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 422.1(M+H⁺).

Example 183: Synthesis ofN-(3-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.06 (t,J=6.4 Hz, 1H), 7.69-7.48 (m, 7H), 7.29 (d, J=6.0 Hz, 2H), 6.92 (t, J=6.4Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.02 (d, J=6.0 Hz, 2H). MS: m/z 422.1(M+H⁺).

Example 184: Synthesis ofN-(4-cyanobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepare as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.79-8.77 (m, 2H), 8.07-8.06 (m, 2H), 7.66-7.64 (m,2H), 7.58-7.51 (m, 4H), 7.38-7.36 (m, 2H), 4.71 (s, 2H), 4.14 (s, 2H).MS: m/z 421.9 (M+H⁺).

Example 185: Synthesis of2-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (brs, 1H), 8.52 (d, J=4.0 Hz, 2H), 7.91-7.79(m, 2H), 7.72-7.64 (m, 2H), 7.64-7.50 (m, 4H), 7.44-7.35 (m, 1H),7.36-7.25 (m, 2H), 6.95 (t, J=5.6 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.29(d, J=6.0 Hz, 2H), 3.80 (s, 3H). MS: m/z 454.9 (M+H⁺).

Example 186: Synthesis of3-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.51 (d, J=4.5 Hz, 2H), 8.04 (t,J=6.6 Hz, 1H), 7.82-7.79 (m, 2H), 7.65-7.43 (m, 6H), 7.29 (d, J=5.1 Hz,2H), 6.93 (t, J=6.9 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.02 (d, J=6.0 Hz,2H), 3.84 (s, 3H). MS: m/z 455.1 (M+H⁺).

Example 187: Synthesis of4-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.18 (brs, 1H), 8.52 (d, J=6.0 Hz, 2H), 8.04 (t,J=6.4 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.66 (d, J=9.2 Hz, 2H), 7.57 (d,J=9.2 Hz, 2H), 7.40 (d, J=6.0 Hz, 2H), 7.31 (d, J=6.0 Hz, 2H), 6.92 (t,J=6.0 Hz, 1H), 4.35 (d, J=5.6 Hz, 2H), 4.02 (d, J=6.4 Hz, 2H), 3.83 (s,3H). MS: m/z 454.9 (M+H⁺).

Example 188: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.20 (s, 1H), 8.52 (d, J=4.5 Hz, 2H), 8.12-8.08(m, 1H), 7.68-7.44 (m, 8H), 7.32 (d, J=5.7 Hz, 2H), 6.95-6.91 (m, 1H),4.35 (d, J=5.4 Hz, 2H), 4.09 (d, J=6.3 Hz, 2H). MS: m/z 465.1 (M+H⁺).

Example 189: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.08-8.04(m, 1H), 7.65-7.54 (m, 8H), 7.29 (d, J=6.0 Hz, 2H), 6.95-6.89 (m, 1H),4.35 (d, J=6.0 Hz, 2H), 4.06 (d, J=6.0 Hz, 2H). MS: m/z 464.9 (M+H⁺).

Example 190: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-(2-Dimethylamino-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.18 (s, 1H), 8.52 (d, J=6.4 Hz, 2H), 8.06(t, J=6.6 Hz, 1H), 7.66-7.63 (m, 4H), 7.56 (d, J=8.8 Hz, 2H), 7.47 (d,J=8.0 Hz, 2H), 7.29 (d, J=4.8 Hz, 2H), 6.92 (t, J=5.6 Hz, 1H), 4.35 (d,J=6.0 Hz, 2H), 4.04 (d, J=6.8 Hz, 2H). MS: m/z 464.9 (M+H⁺).

Example 191: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.20 (s, 1H), 8.51 (d, J=4.4 Hz, 2H), 8.01-7.98(m, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.49 (d, J=7.6Hz, 1H), 7.41-7.29 (m, 5H), 6.94-6.91 (m, 1H), 4.35 (d, J=5.2 Hz, 2H),3.99 (d, J=6.0 Hz, 2H). MS: m/z 481.1 (M+H⁺)

Example 192: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethoxy-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.21 (s, 1H), 8.51 (d, J=4.8 Hz, 2H), 8.05 (t,J=6.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.42 (t,J=8.0 Hz, 1H), 7.30-7.20 (m, 5H), 6.95-6.92 (m, 1H), 4.34 (d, J=6.0 Hz,2H), 4.01 (d, J=6.4 Hz, 2H). MS: m/z 481.1 (M+H⁺).

Example 193: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethoxy-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.21 (s, 1H), 8.51 (d, J=5.7 Hz, 2H), 8.01-7.97(m, 1H), 7.66-7.55 (m, 4H), 7.37-7.25 (m, 6H), 6.96-6.92 (m, 1H), 4.35(d, J=6.3 Hz, 2H), 3.97 (d, J=6.6 Hz, 2H). MS: m/z 481.1 (M+H⁺).

Example 194: Synthesis ofN-(2-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of 2-dimethylamino-benzonitrile (300 mg, 2.1 mmol)in CH₃OH (5 mL) and NH₄OH (1 mL) was added Raney-Ni (100 mg). Thereaction mixture was stirred at room temperature overnight under H₂balloon atmosphere. The suspension was filtered and the filter cake waswashed with CH₃OH (20 mL). The combined filtrate were concentrated todryness to give the (2-aminomethyl-phenyl)-dimethyl-amine (200 mg,yield: quantitative) as colorless oil.

Step 2: Step 2 was prepared as described in exampleN-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.18 (s, 1H), 8.53 (s, 2H), 7.75 (t, J=6.4Hz, 1H), 7.69 (d, J=2.8 Hz, 2H), 7.67 (d, J=2.4 Hz, 2H), 7.35-7.30 (m,3H), 7.21-7.17 (m, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.70 (t, J=6.6 Hz, 1H),6.93 (t, J=6.4 Hz, 1H), 4.35 (d, J=6.0 Hz, 1H), 3.99 (d, J=6.4 Hz, 1H),2.50 (s, 6H). MS: m/z 439.9 (M+H⁺).

Example 195: Synthesis ofN-(3-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of 3-amino-benzonitrile (1.0 g, 8.5 mmol) and HCHO(2.1 g, 69.0 mmol) in CH₃CN (20 mL) was added NaBH₃CN (2.7 g, 42.5mmol). The reaction was stirred at room temperature for 2 hrs. HAc (100mL) was added to adjust pH to 7. The resulting reaction mixture wasstirred for 2 hrs. KOH (1 N, 100 mL) was added and the mixture wasextracted with EtOAc (100 mL*2). The organic layer was washed with andbrine (80 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column eluting with PE/EtOAc (10:1) to give the3-dimethylamino-benzonitrile (1.3 g, 100%) as colorless oil. MS: m/z147.3 (M+H⁺).

Step 2, 3: Step 2 and 3 was prepared as described in exampleN-(2-dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ=9.16 (s, 1H), 8.51 (d, J=4.8 Hz, 2H), 7.82(t, J=6.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.29(d, J=5.6 Hz, 2H), 7.07 (t, J=8.0 Hz, 1H), 6.91 (t, J=2.0 Hz, 1H),6.58-6.51 (m, 3H), 4.34 (d, J=6.0 Hz, 2H), 3.86 (d, J=6.0 Hz, 2H), 2.82(s, 6H). MS: m/z 440.0 (M+H⁺).

Example 196: Synthesis ofN-(4-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.16 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.71-7.55(m, 5H), 7.29 (d, J=5.1 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.92-6.90 (m,1H), 6.62 (d, J=8.1 Hz, 2H), 4.35 (d, J=6.0 Hz, 2H), 3.78 (d, J=6.0 Hz,2H), 2.84 (s, 6H). MS: m/z 440.1 (M+H⁺).

Example 197: Synthesis ofN-(4-Methanesulfonyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.52 (s, 2H), 8.10 (t, J=6.0 Hz,1H), 7.82 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz,2H), 7.50 (d, J=8.0 Hz, 2H), 7.30 (d, J=3.6 Hz, 2H), 6.91 (t, J=4.8 Hz,1H), 4.34 (d, J=5.6 Hz, 2H), 4.06 (d, J=6.0 Hz, 2H), 3.15 (s, 3H). MS:m/z 474.9 (M+H⁺).

Example 198: Synthesis ofN,N-dimethyl-4-((4-(3-(pyridin-4-ylmethyl)ureido)phenylsulfonamido)methyl)benzenesulfonamide

Step 1: To a solution of 4-cyano-benzenesulfonyl chloride (1.0 g, 5.0mmol) in DCM (20 mL) was added TEA (1.5 g, 15.0 mmol) at 0° C. Thereaction was stirred for 1 hr at room temperature. The reaction wasconcentrated to dryness in vacuum and the residue was purified by silicagel column eluting with PE/EtOAc (10:1) to give the4-cyano-N,N-dimethyl-benzenesulfonamide (720 mg, 65%) as a white solid.

Step 2, 3: Step 2 and 3 was prepared as described in exampleN-(2-dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (300 MHz, DMSO-d₆) δ=9.17 (s, 1H), 8.50 (d, J=5.4 Hz, 2H), 8.12(t, J=6.6 Hz, 1H), 4.34 (d, J=8.7 Hz, 4H), 7.55-7.48 (m, 4H), 7.28 (d,J=5.4 Hz, 2H), 6.91 (t, J=6.0 Hz, 1H), 4.33 (d, J=5.7 Hz, 2H), 4.08 (d,J=6.3 Hz, 2H), 2.49 (s, 6H). MS: m/z 503.9 (M+H⁺).

Example 199: Synthesis ofN-(4-((dimethylamino)methyl)benzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

Step 1: To a solution of 4-formyl-benzonitrile (1.30 g, 10 mmoL),dimethylamine.HCl (1.63 g, 20 mmoL) and Et₃N (3 mL, 20 mmoL) in EtOH (15mL) was added (i-PrO)₄Ti (6 mL, 20 mmoL) dropwise at room temperature.Then the mixture was stirred at room temperature for 19 hrs. Thereaction mixture was poured into aqueous ammonia (30 mL, 30%). Theresulting inorganic precipitate was filtered. The filtrate was extractedwith DCM (50 mL*2). The extracts were dried over Na₂SO₄ and concentratedto dryness in vacuum. The residue was purified by silica gel columneluting with DCM/MeOH (100:1) to give 4-dimethylaminomethyl-benzonitrile(500 mg, yield: 31%) as white oil. ¹H NMR (300 MHz, DMSO-d₆): δ=7.77 (d,J=7.2 Hz, 2H), 7.49 (d, J=7.5 Hz, 2H), 3.45 (s, 2H), 2.14 (s, 6H). MS:m/z 161.4 (M+H⁺).

Step 2: To a solution of 4-dimethylaminomethyl-benzonitrile (240 mg, 1.5mmoL) in MeOH (5 mL) was added Raney-Ni (40 mg) under H₂ atmosphere(balloon) at room temperature. Then the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was filtered to remove thecatalyst and the filtrate was concentrated to give4-dimethylaminomethyl-benzylamine (crude) as colorless oil. MS: m/z165.1 (M+H⁺).

Step 3: To a solution of 4-dimethylaminomethyl-benzylamine (220 mg, 1.3mmoL) in pyridine (5 mL) was added4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonyl chloride (524 mg, 1.6mmoL) at room temperature. Then the mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated to drynessin vacuum. The residue was purified by silica gel column eluting withDCM/MeOH (2:1) to give the crude product. Then the crude product waspurified by Prep-HPLC to giveN-(4-dimethylaminomethyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(23 mg, yield: 4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.16(s, 1H), 8.51 (d, J=6.4 Hz, 2H), 7.90 (t, J=6.4 Hz, 1H), 7.64 (d, J=8.8Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.18-7.16 (m,4H), 6.92 (t, J=5.6 Hz, 1H), 4.34 (d, J=6 Hz, 2H), 3.92 (d, J=6.4 Hz,2H), 3.33 (overlap, 2H), 2.10 (s, 6H). MS: m/z 454.0 (M+H⁺).

Example 200: Synthesis ofN-(4-Methoxymethyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of 4-formyl-benzonitrile (1.51 g, 11.5 mmoL) inMeOH (15 mL) was added NaBH₄ (0.51 g, 13.4 mmoL) at 0° C. Then themixture was stirred at this temperature for 1.5 hrs. The reaction wasquenched with H₂O (7.5 mL) and the resulting mixture was concentrated toremove most of the MeOH. Then the residue was poured into H₂O (20 mL)and extracted with EtOAc (30 mL*2). The combined EtOAc extracts werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated to give4-hydroxymethyl-benzonitrile (1.26 g, yield: 82%) as colorless oil.

Step 2: To a solution of 4-hydroxymethyl-benzonitrile (1.26 g, 9.5 mmoL)in THF (10 mL) was added NaH (0.76 g, 19 mmoL) at −10° C., and thesuspension was stirred at this temperature for 0.5 hrs and followed bythe addiotn of MeI (2.7 g, 19 mmol). Then the mixture was stirred atthis temperature for 2 hrs. The reaction was quenched with H₂O (50 mL).The mixture was extracted with EtOAc (25 mL*3). The combined EtOAcextracts were dried over Na₂SO₄ and concentrated to give4-methoxymethyl-benzonitrile (crude) as yellow oil.

Step 3: To a suspension of LiAlH₄ (1.1 g, 28.9 mmoL) in THF (15 mL) wasadded dropwise a solution of 4-methoxymethyl-benzonitrile (1.4 g, 9.5mmoL) in THF (15 mL) at 0° C. Then the mixture was stirred at roomtemperature for 19 hrs. The reaction was quenched with the dropwiseaddition of H₂O (1.2 mL) at 0° C. and followed by an aqueous NaOH (15%,1.2 mL) and H₂O (3.6 mL). The mixture was stirred at room temperaturefor 30 min and the precipitate was filtered and the pad was washed withEtOAc (10 mL). The filtrate was concentrated to give4-methoxymethyl-benzylamine (1.3 g, yield: 90%) as yellow oil.

Step 4: To a solution of 4-methoxymethyl-benzylamine (251 mg, 1.7 mmoL)in pyridine (5 mL) was added4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonyl chloride (650 mg, 2.0mmoL) at 0° C. and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated to dryness in vacuum.The residue was purified by silica gel column eluting with DCM/MeOH(5:1) to give the yellow crude product. Then the crude was purified byPrep-HPLC to giveN-(4-methoxymethyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(111 mg, yield: 15%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.18(s, 1H), 8.51 (d, J=6 Hz, 2H), 7.91 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.29 (d, J=6 Hz, 2H), 7.23-7.19 (m,4H), 6.92 (t, J=5.6 Hz, 1H), 4.35 (d, J=6.8 Hz, 4H), 3.92 (d, J=6.4 Hz,2H), 3.24 (s, 3H). MS: m/z 440.9 (M+H⁺).

Example 201: Synthesis ofN-(1-phenylethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.78-8.76 (m, 2H), 8.05-8.04 (m, 2H), 7.57-7.54 (m,2H), 7.45-7.43 (m, 2H), 7.17-7.11 (m, 5H), 4.69 (s, 2H), 4.39-4.35 (m,1H), 1.30 (d, J=8.0 Hz, 3H). MS: m/z 410.9 (M+H⁺).

Example 202: Synthesis ofN-Pyridin-4-ylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.26 (brs, 1H), 8.52-8.46 (dd, J=4.4 Hz, 4H), 8.11(brs, 1H), 7.67-7.57 (dd, J=8.4 Hz, 4H), 7.30-7.26 (dd, J=4.8 Hz, 4H),6.95 (brs, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.98 (d, J=6.0 Hz, 2H). MS:m/z397.9 (M+H⁺)

Example 203: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.23 (s, 1H), 8.50 (d, J=5.4 Hz, 2H), 7.84 (d,J=8.2 Hz, 1H), 7.73 (d, J=5.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.32 (d,J=5.6 Hz, 2H), 7.15-7.07 (m, 3H), 7.03 (d, J=7.6 Hz, 1H), 6.95 (t, J=5.6Hz, 1H), 4.36 (d, J=5.6 Hz, 3H), 2.63 (overlap, 2H), 1.77 (s, 1H), 1.55(d, J=6.0 Hz, 3H). MS: m/z 436.9 (M+H⁺).

Example 204: Synthesis ofN,N-Dimethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.48 (d, J=5.2 Hz, 2H), 7.68-7.62 (m, 4H), 7.41 (d,J=4.8 Hz, 2H), 4.47 (s, 2H), 2.65 (s, 6H). MS:m/z 335.0 (M+H⁺).

Example 205: Synthesis ofN,N-Diethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.22 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),7.66-7.56 (m, 4H), 7.29 (d, J=6.0 Hz, 2H), 6.92 (t, J=6.0 Hz, 1H), 4.34(d, J=6.4 Hz, 2H), 3.11 (q, J=7.2 Hz, 4H), 1.02 (t, J=7.2 Hz, 6H). MS:m/z 363.0 (M+H⁺).

Example 206: Synthesis ofN-(2-Hydroxy-ethyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.27 (brs, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.62 (s,4H), 7.29 (d, J=5.6 Hz, 2H), 6.95-6.93 (brs, 1H), 4.79-4.77 (brs, 1H),4.35 (d, J=5.6 Hz, 2H), 3.50 (dd, J=11.6, 6.0 Hz, 2H), 2.95-2.92 (t,2H), 2.67 (s, 3H). MS:m/z 364.9 (M+H⁺)

Example 207: Synthesis ofN-Cyclopentyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H),7.67-7.57 (m, 4H), 7.29 (d, J=6.0 Hz, 2H), 6.94 (t, J=6.0 Hz, 1H), 4.34(d, J=6.0 Hz, 2H), 4.22-4.11 (m, 1H), 2.59 (s, 3H), 1.55-1.43 (m, 4H),1.42-1.34 (m, 2H), 1.32-1.20 (m, 2H). MS: m/z 389.1 (M+H⁺).

Example 208: Synthesis ofN-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.50-8.48 (m, 2H), 7.77-7.74 (m, 2H), 7.69-7.65 (m,2H), 7.43-7.41 (m, 2H), 7.35-7.31 (m, 5H), 4.49 (s, 2H), 4.12 (s, 2H),2.56 (s, 3H). MS: m/z 411.0 (M+H⁺).

Example 209: Synthesis ofN-(2-Fluoro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.29 (s, 1H), 8.49 (d, J=7.5 Hz, 2H), 7.72-7.65(m, 4H), 7.41-7.39 (m, 2H), 7.30 (d, J=5.6 Hz, 2H), 7.24-7.20 (m, 2H),6.96 (t, J=6.0 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H), 4.13 (s, 2H), 2.53-2.49(m, 3H). MS: m/z 428.9 (M+H⁺)

Example 210: Synthesis ofN-(2-Chloro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.32 (s, 1H), 8.52 (d, J=6.0 Hz, 2H), 7.74-7.66(m, 4H), 7.47 (d, J=4.8 Hz, 2H), 7.39-7.30 (m, 4H), 6.97 (t, J=6.0 Hz,1H), 4.36 (d, J=6.4 Hz, 2H), 4.19 (s, 2H), 2.55-2.49 (m, 3H). MS: m/z444.9 (M+H⁺)

Example 211: Synthesis of1-[4-(Piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.42 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H), 7.66(d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.08(t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 2.80-2.64 (m, 8H). MS: m/z376.0 (M+H⁺).

Example 212: Synthesis ofN-Cyclobutylmethyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of C-cyclobutyl-methylamine hydrochloride (1.0 g,8.2 mmol) in THF (50 mL) was added Boc₂O (1.97 g, 9.0 mmol) and TEA (1.7g, 16.4 mmol). After stirring at room temperature overnight, thereaction mixture was evaporated in vacuum. The residue was purified bysilica gel column chromatograph eluting with PE/EtOAc (10:1) to affordcyclobutylmethyl-carbamic acid tert-butyl ester (1.25 g, 82%) ascolorless oil. ¹H NMR (400 MHz, CD₃Cl): δ=4.48 (s, 1H), 3.14 (t, J=6.4Hz, 2H), 2.46-2.39 (m, 1H), 2.07-2.00 (m, 2H), 1.93-1.84 (m, 2H),1.71-1.64 (m, 2H), 1.44 (s, 9H).

Step 2: To a solution of cyclobutylmethyl-carbamic acid tert-butyl ester(1.25 g, 6.75 mmol) in THF (50 mL) was added LiAlH₄ (1.28 g, 33.8 mmol).After stirring at reflux overnight, the reaction was quenched with H₂O(2 mL). Then the mixture was dried over anhydrous Na₂SO₄ and filtered.The filtrate was evaporated in vacuum to affordcyclobutylmethyl-methyl-amine as a crude product which was used for nextstep without further purification.

Step 3: To a solution of 4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonicacid (200 mg, 0.65 mmol) in DCM (15 mL) was added (COCl)₂ (165 mg, 1.3mmol) and DMF (2 drops). After stirring at room temperature for 5 hrs,the reaction mixture was evaporated in vacuum. The residue was disslovedin DMF (5 mL) and then cyclobutylmethyl-methyl-amine (97 mg, 0.98 mmol)and DIPEA (252 mg, 1.95 mmol) were added. After stirring at roomtemperature overnight, the residue was purified by pre-HPLC to affordN-cyclobutylmethyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(21 mg, 8%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (dd,J=4.8, 1.6 Hz, 2H), 7.67 (d, J=9.2 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.41(d, J=6.0 Hz, 2H), 4.47 (s, 2H), 2.97 (d, J=7.2 Hz, 2H), 2.65 (s, 3H),2.59-2.51 (m, 1H), 2.08-2.01 (m, 2H), 1.95-1.82 (m, 2H), 1.78-1.71 (m,2H). MS: m/z 388.9 (M+H)⁺.

Example 213: Synthesis ofN-Cyclohexyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of cyclohexylamine (1.0 g, 10.1 mmol) in DCM (50mL) was added Boc₂O (2.2 g, 10.1 mmol) and TEA (2.04 g, 20.2 mmol).After stirring at room temperature overnight, the reaction mixture wasevaporated in vacuum. The residue was purified by silica gel columnchromatograph eluting with PE/EtOAc (10:1) to afford cyclohexyl-carbamicacid tert-butyl ester (1.93 g, 97%) as a white solid.

Step 2: To a solution of cyclohexyl-carbamic acid tert-butyl ester (1.0g, 5 mmol) in THF (30 mL) was added LiAlH₄ (760 mg, 20 mmol). Afterstirring at reflux overnight, the reaction was quenched with H₂O (2 mL).Then the mixture was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was evaporated in vacuum to afford cyclohexyl-methyl-amine as acrude product which was used for next step without further purification.

Step 3: To a solution of 4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonicacid (150 mg, 0.49 mmol) in DCM (15 mL) was added (COCl)₂ (124 mg, 0.98mmol) and DMF (2 drops). After stirring at room temperature for 5 hrs,the reaction mixture was evaporated in vacuum. The residue was disslovedin DMF (5 mL) and then cyclohexyl-methyl-amine (83 mg, 0.74 mmol) andDIPEA (190 mg, 1.47 mmol) were added. After stirring at room temperatureovernight, the residue was purified by pre-HPLC to affordN-cyclohexyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(21 mg, 11%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.31 (s,1H), 8.50 (d, J=5.6 Hz, 2H), 7.65-7.58 (m, 4H), 7.29 (d, J=4.8 Hz, 2H),7.00 (s, 1H), 4.34 (d, J=6.0 Hz, 2H), 3.62-3.54 (m, 1H), 2.63 (s, 3H),1.67-1.64 (m, 2H), 1.53-1.50 (m, 1H), 1.32-1.19 (m, 7H). MS: m/z 403.0(M+H)⁺.

Example 214: Synthesis ofN-Cyclopentyl-N-isobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of cyclopentylamine (500 mg, 5.9 mmol) in DCM (10mL) was added isobutyryl chloride (629 mg, 5.9 mmol) and DIPEA (1.1 g,8.6 mmol). After stirring at room temperature overnight, the reactionmixture was evaporated in vacuum. The residue was purified by silica gelcolumn chromatograph eluting with PE/EtOAc (3:1) to affordN-cyclopentyl-isobutyramide (878 mg, 96%) as a yellow solid.

Step 2: To a solution of N-cyclopentyl-isobutyramide (300 mg, 1.9 mmol)in THF (20 mL) was added LiAlH₄ (289 mg, 7.6 mmol). After stirring atreflux overnight, the reaction was quenched with H₂O (1 mL). Then themixture was dried over anhydrous Na₂SO₄ and filtered. The filtrate wasadjusted to pH=3 with conc. HCl and evaporated in vacuum to affordcyclopentyl-isobutyl-amine hydrochloride as a crude product which wasused for next step without further purification.

Step 3: To a solution of cyclopentyl-isobutyl-amine hydrochloride (340mg, 1.9 mmol) in DCM (10 mL) was added 4-nitro-benzenesulfonyl chloride(463 mg, 2.1 mmol) and TEA (384 mg, 3.8 mmol). After stirring at roomtemperature overnight, the reaction mixture was evaporated in vacuum.The residue was purified by silica gel column chromatograph eluting withPE/EtOAc (10:1) to affordN-cyclopentyl-N-isobutyl-4-nitro-benzenesulfonamide (110 mg, 18%) asyellow oil. ¹H NMR (400 MHz, CD₃OD): δ=8.40 (d, J=9.2 Hz, 2H), 8.07 (d,J=8.8 Hz, 2H), 4.16-4.09 (m, 1H), 2.98 (d, J=7.6 Hz, 2H), 2.09-2.03 (m,1H), 1.64-1.60 (m, 4H), 1.50-1.41 (m, 4H), 0.95 (d, J=6.8 Hz, 6H).

Step 4: To a solution ofN-cyclopentyl-N-isobutyl-4-nitro-benzenesulfonamide (110 mg, 0.37 mmol)in MeOH (10 mL) was added 10% Pd/C (39 mg, 0.04 mmol). After stirring atroom temperature under balloon hydrogen atmosphere overnight, thereaction mixture was filtered. The filtrate was evaporated in vacuum toafford 4-amino-N-cyclopentyl-N-isobutyl-benzenesulfonamide as a crudeproduct which was used for next step without further purification.

Step 5: To a solution of4-amino-N-cyclopentyl-N-isobutyl-benzenesulfonamide in DCM (5 mL) wasadded phenyl chloroformate (116 mg, 0.74 mmol) and DIPEA (95.6 mg, 0.74mmol). After stirring at room temperature overnight, the reactionmixture was evaporated in vacuum. The residue was purified by silica gelcolumn chromatograph eluting with PE/EtOAc (3:1) to afford[4-(cyclopentyl-isobutyl-sulfamoyl)-phenyl]-carbamic acid phenyl esteras the crude product.

Step 6: To a solution of[4-(cyclopentyl-isobutyl-sulfamoyl)-phenyl]-carbamic acid phenyl ester(crude, 0.35 mmol) in dioxane (10 mL) was addedC-pyridin-4-yl-methylamine (56.8 mg, 0.53 mmol) and DIPEA (90.5 mg, 0.7mmol). After stirring at 90° C. for 5 hrs, the reaction mixture wasconcentrated in vacuum. The residue was purified by pre-HPLC to affordN-cyclopentyl-N-isobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(40 mg, 27%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.21 (s,1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.65 (d, J=9.2 Hz, 2H), 7.58 (d,J=8.8 Hz, 2H), 7.29 (d, J=5.6 Hz, 2H), 6.92 (t, J=6.0 Hz, 1H), 4.34 (d,J=6.0 Hz, 2H), 4.00-3.96 (m, 1H), 2.77 (d, J=7.2 Hz, 2H), 2.00-1.94 (m,1H), 1.51-1.26 (m, 8H), 0.88 (d, J=6.8 Hz, 6H). MS: m/z 431.0 (M+H)⁺.

Example 215: Synthesis ofN-Cyclopentyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

Step 1: To a solution of cyclopentylamine (1.0 g, 11.7 mmol) in DCM (50mL) was added Ac₂O (1.32 g, 12.9 mmol) and TEA (2.37 g, 23.4 mmol).After stirring at room temperature overnight, the reaction mixture wasevaporated in vacuum. The residue was purified by silica gel columnchromatograph eluting with PE/EtOAc (1:1) to affordN-cyclopentyl-acetamide (1.24 g, 83%) as colorless oil. ¹H NMR (400 MHz,CDCl₃): δ=5.62 (s, 1H), 4.24-4.15 (m, 1H), 2.02-1.96 (m, 5H), 1.69-1.53(m, 4H), 1.41-1.33 (m, 2H).

Step 2: To a solution of N-cyclopentyl-acetamide (1.35 g, 10.6 mmol) inTHF (30 mL) was added LiAlH₄ (1.6 g, 42.4 mmol). After stirring atreflux overnight, the reaction was quenched with H₂O (2 mL). Then themixture was dried over anhydrous MgSO₄ and filtered. The filtrate wasadjusted to pH=3 with conc.HCl and evaporated in vacuum to affordcyclopentyl-ethyl-amine hydrochloride as a crude product which was usedfor next step without further purification.

Step 3: To a solution of cyclopentyl-ethyl-amine hydrochloride (820 mg,3.6 mmol) in DCM (15 mL) was added 4-nitro-benzenesulfonyl chloride (600mg, 3.6 mmol) and TEA (729 mg, 7.2 mmol). After stirring at roomtemperature overnight, the reaction mixture was evaporated in vacuum.The residue was purified by silica gel column chromatograph eluting withPE/EtOAc (10:1) to affordN-cyclopentyl-N-ethyl-4-nitro-benzenesulfonamide (600 mg, 56%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.38 (d, J=8.8 Hz, 2H), 8.10(d, J=8.4 Hz, 2H), 4.19-4.11 (m, 1H), 3.15 (q, J=6.8 Hz, 2H), 1.65-1.52(m, 4H), 1.46-1.39 (m, 2H), 1.35-1.28 (m, 2H), 1.19 (t, J=6.8 Hz, 3H).

Step 4: To a solution ofN-cyclopentyl-N-ethyl-4-nitro-benzenesulfonamide (250 mg, 0.84 mmol) inEtOH (15 mL) was added 10% Pd/C (89 mg, 0.08 mmol). After stirringovernight at room temperature under balloon hydrogen atmosphere, thereaction mixture was filtered. The filtrate was evaporated in vacuum toafford 4-amino-N-cyclopentyl-N-ethyl-benzenesulfonamide as a crudeproduct which was used for next step without further purification.

Step 5: To a solution of4-amino-N-cyclopentyl-N-ethyl-benzenesulfonamide (226 mg, 0.84 mmol) inDCM (10 mL) was added phenyl chloroformate (263 mg, 1.68 mmol) and DIPEA(217 mg, 1.68 mmol). After stirring at room temperature overnight, thereaction mixture was evaporated in vacuum. The residue was purified bysilica gel column chromatograph eluting with PE/EtOAc (4:1) to afford[4-(cyclopentyl-ethyl-sulfamoyl)-phenyl]-carbamic acid phenyl ester (210mg, 64%) as yellow oil.

Step 6: To a solution of[4-(cyclopentyl-ethyl-sulfamoyl)-phenyl]-carbamic acid phenyl ester (150mg, 0.38 mmol) in dioxane (10 mL) was added C-pyridin-4-yl-methylamine(61.6 mg, 0.57 mmol) and DIPEA (98 mg, 0.76 mmol). After stirring at 90°C. overnight, the reaction mixture was concentrated in vacuum. Theresidue was purified by pre-HPLC to affordN-Cyclopentyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(30 mg, 19%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.19 (s,1H), 8.50 (dd, J=4.4, 1.2 Hz, 2H), 7.65 (d, J=9.2 Hz, 2H), 7.58 (d,J=9.2 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 6.91 (t, J=6.0 Hz, 1H), 4.34 (d,J=5.6 Hz, 2H), 4.09-4.01 (m, 1H), 3.04 (q, J=7.2 Hz, 2H), 1.58-1.51 (m,4H), 1.43-1.37 (m, 2H), 1.29-1.18 (m, 2H), 1.16 (t, J=7.2 Hz, 3H). MS:m/z 403.0 (M+H)⁺.

Example 216: Synthesis ofN-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(2-(trifluoromethyl)benzyl)benzenesulfonamide

Step 1: To a stirring solution of 2-trifluoromethyl-benzylamine (2.5 g,14.3 mmol) in dioxane/H₂O (80 mL/40 mL) was added NaOH (2.3 g, 57.1mmol) and Boc₂O (3.8 g, 17.1 mmol). After stirring at room temperaturefor 16 hrs, the reaction mixture was poured to water (100 mL) andextracted with EtOAc (50 mL*2). The combined organic layer was washedwith brine (50 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column eluting with PE/EtOAc (40:1) to give(2-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (2.0 g, yield:51%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=7.63 (d, J=7.6 Hz,1H), 7.59-7.51 (m, 2H), 7.37 (t, J=7.8 Hz, 1H), 4.94 (brs, 1H), 4.50 (d,J=6.0 Hz, 2H), 1.46 (s, 9H).

Step 2: To a solution of (2-trifluoromethyl-benzyl)-carbamic acidtert-butyl ester (2.0 g, 7.3 mmol) in THF (20 mL) was added LAH (830 mg,21.8 mmol) portionwise at 0° C. After stirring at 70° C. for 16 hrs, H₂O(0.8 mL), 15% NaOH (0.8 mL) and H₂O (2.5 mL) were then added dropwise at0° C. The mixture was stirred at room temperature for another 20 min,dried over MgSO₄ and filtered. The filtrate was concentrated andpurified by silica gel column eluting with DCM/MeOH (30:1) to givemethyl-(2-trifluoromethyl-benzyl)-amine (900 mg, yield: 66%) as yellowoil. ¹H NMR (400 MHz, CDCl₃): δ=7.63 (t, J=8.0 Hz, 2H), 7.52 (t, J=7.6Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 3.91 (s, 2H), 2.48 (s, 3H).

Step 3: This step was similar to general procedure ofN-(2-methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.32 (s, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H),7.78-7.67 (m, 7H), 7.54 (t, J=7.4 Hz, 1H), 7.31 (d, J=6.0 Hz, 2H), 6.98(t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 4.26 (s, 2H), 2.56 (s, 3H).MS: m/z 478.9 (M+H⁺).

Example 217: Synthesis ofN-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-benzenesulfonamide

The title compound was prepared as described in exampleN-methyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.30 (s, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H),7.73-7.66 (m, 4H), 7.55-7.37 (m, 4H), 7.30 (d, J=6.0 Hz, 2H), 6.96 (t,J=5.6 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H), 4.16 (s, 2H), 2.53-2.49 (m, 3H).MS: m/z 494.9 (M+H⁺).

Example 218: Synthesis ofN-(2-Methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

To a stirring solution of4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonyl chloride (500 mg, 1.5mmol) in pyridine (5 mL) was added (2-methoxy-benzyl)-methyl-amine (230mg, 1.5 mmol). After stirring at room temperature for 1 h, the reactionmixture was concentrated. The residue was purified by silica gel columneluting with DCM/MeOH (10:1) and Prep-HPLC (NH₄HCO₃) to giveN-(2-methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide(15 mg, yield: 2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.27(s, 1H), 8.51 (dd, J=4.4, 1.2 Hz, 2H), 7.71-7.64 (m, 4H), 7.31-7.27 (m,4H), 7.01-6.93 (m, 3H), 4.36 (d, J=6.0 Hz, 2H), 4.05 (s, 2H), 3.74 (s,3H), 2.53 (s, 3H). MS: m/z 440.9 (M+H⁺).

Example 219: Synthesis ofN-Benzyl-N-isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.35 (brs, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.70 (d,J=8.4 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.41 (d, J=7.2 Hz, 2H), 7.37-7.28(m, 4H), 7.24 (t, J=7.2 Hz, 1H), 7.01 (t, J=6.0 Hz, 1H), 4.39-4.31 (m,4H), 4.05-3.96 (m, 1H), 0.83 (d, J=6.8 Hz, 6H). MS: m/z 439.0 (M+H⁺).

Example 220: Synthesis ofN-Benzyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.29 (brs, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H), 7.69(d, J=9.2 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.39-7.25 (m, 7H), 6.97 (t,J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.27 (s, 2H), 3.07 (q, J=7.2 Hz,2H), 0.82 (t, J=7.2 Hz, 3H). MS: m/z 425.0 (M+H⁺).

Example 221: Synthesis ofN-Benzyl-N-cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.33 (brs, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.72 (d,J=9.2 Hz, 2H), 7.63 (d, J=9.2 Hz, 2H), 7.37-7.23 (m, 7H), 6.98 (t, J=6.0Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.28 (s, 2H), 2.04-1.96 (m, 1H),0.56-0.50 (m, 2H), 0.50-0.44 (m, 2H). MS: m/z 436.9 (M+H⁺).

Example 222: Synthesis ofN-Benzyl-N-propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.35 (brs, 1H), 8.51 (dd, J=4.4, 1.2 Hz, 2H), 7.71(d, J=9.2 Hz, 2H), 7.63 (d, J=9.2 Hz, 2H), 7.38-7.24 (m, 7H), 7.01 (t,J=6.0 Hz, 1H), 4.35 (d, J=6.4 Hz, 2H), 4.25 (s, 2H), 2.96 (t, J=7.6 Hz,2H), 1.30-1.16 (m, 2H), 0.62 (t, J=7.2 Hz, 3H). MS: m/z 439.0 (M+H⁺).

Example 223: Synthesis ofN,N-Dibenzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.27 (brs, 1H), 8.52 (d, J=5.6 Hz, 2H), 7.74 (d,J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.31 (d, J=6.0 Hz, 2H), 7.25-7.15(m, 6H), 7.12-7.04 (m, 4H), 6.95 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz,2H), 4.24 (s, 4H). MS: m/z 486.9 (M+H⁺).

Example 224: Synthesis ofN-Methyl-N-(2-methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆):δ=9.29 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.74-7.66 (m,4H), 7.30 (d, J=5.6 Hz, 2H), 7.22-7.18 (m, 4H), 6.96 (t, J=6.8 Hz, 1H),4.36 (d, J=6.0 Hz, 2H), 4.04 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H). MS:m/z 425.0 (M+H⁺).

Example 225: Synthesis ofN-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide

Step 1: To a solution of 4-nitro-benzenesulfonyl chloride (2.2 g, 10.0mmol) and Et₃N (2.9 mL, 20.0 mmol) in DCM (30 mL) was added benzylamine(1.4 g, 13.0 mmol) at 0° C. After stirring at room temperature for 1 h,the reaction mixture was diluted with DCM (30 mL) and washed with aq.HCl(1 N, 30 mL) and Sat.NaHCO₃ (20 mL). The organic layer was dried overNa₂SO₄ and concentrated. The residue was washed with PE/EtOAc (4:1, 20mL) to give N-benzyl-4-nitro-benzenesulfonamide (1.4 g, yield: 48%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.32-8.28 (m, 2H), 8.01-7.96(m, 2H), 7.28-7.24 (m, 3H), 7.18-7.15 (m, 2H), 4.50 (t, J=5.6 Hz, 1H),4.23 (d, J=6.0 Hz, 2H).

Step 2: A mixture of N-benzyl-4-nitro-benzenesulfonamide (600 mg, 3.9mmol), trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (950mg, 4.1 mmol) and K₂CO₃ (850 mg, 6.2 mmol) in MeCN (10 mL) was sealed ina tube and heated in microwave at 100° C. for 30 min. The reactionmixture was poured to water (20 mL) and extracted with EtOAc (20 mL*2).The combined organic layer was washed with brine (20 mL), dried overNa₂SO₄ and concentrated. The residue was purified by silica gel columneluting with PE/EtOAc (20:1) to giveN-benzyl-4-nitro-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (740 mg,yield: 96%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.38-8.34 (m,2H), 8.03 (d, J=8.8 Hz, 2H), 7.40-7.27 (m, 5H), 4.58 (s, 2H), 3.85 (q,J=9.2 Hz, 2H).

Step 3: To a solution ofN-benzyl-4-nitro-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (740 mg,2.0 mmol) in MeOH/H₂O (30 mL/8 mL) was added Fe (550 mg, 10.0 mmol) andNH₄C (1.1 g, 20.0 mmol). After stirring at 75° C. for 2 hrs, thereaction mixture was concentrated, diluted with EtOAc/H₂O (50 mL/50 mL)and filtered. The organic layer was separated, washed with brine (20mL), dried over Na₂SO₄ and concentrated to give4-amino-N-benzyl-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (650 mg,yield: 96%) as a white solid which was used to the next step withoutfurther purification.

Step 4: To a solution of4-amino-N-benzyl-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide (250 mg,0.7 mmol) and TEA (0.3 mL, 2.2 mmol) in DCM (20 mL) was added phenylchloroformate (150 mg, 0.9 mmol) dropwise at 0° C. After stirring atthis temperature for 30 min, the reaction mixture was diluted with DCM(20 mL) and washed with aq.HCl (1 N, 20 mL) and Sat.NaHCO₃ (20 mL). TheDCM solution was dried over Na₂SO₄ and concentrated to give{4-[benzyl-(2,2,2-trifluoro-ethyl)-sulfamoyl]-phenyl}-carbamic acidphenyl ester (crude) as colorless oil.

Step 5: A mixture of{4-[benzyl-(2,2,2-trifluoro-ethyl)-sulfamoyl]-phenyl}-carbamic acidphenyl ester (crude), C-pyridin-4-yl-methylamine (70 mg, 0.6 mmol) andTEA (0.2 mL, 1.4 mmol) in MeCN (15 mL) was stirred at 80° C. for 16 hrsand then concentrated. The residue was purified by silica flash columneluting with DCM/MeOH (DCM to 10:1) to giveN-benzyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide(70 mg, yield: 20% for two steps) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ=9.31 (s, 1H), 8.51 (dd, J=4.4, 1.6 Hz, 2H), 7.79 (d, J=8.8Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.35-7.27 (m, 5H), 7.23-7.20 (m, 2H),6.97 (t, J=6.0 Hz, 1H), 4.37-4.34 (m, 4H), 3.98 (q, J=9.2 Hz, 2H). MS:m/z 478.9 (M+H⁺).

Example 226: Synthesis ofN-Benzyl-N-phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.29 (brs, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.61 (d,J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.30 (d, J=5.2 Hz, 2H), 7.27-7.21(m, 6H), 7.21-7.14 (m, 2H), 7.05 (d, J=5.2 Hz, 2H), 6.96 (t, J=6.0 Hz,1H), 4.76 (s, 2H), 4.35 (d, J=6.0 Hz, 2H). MS: m/z 472.9 (M+H⁺).

Example 227: Synthesis ofPyridin-4-ylmethyl-3-[4-(pyrrolidine-1-sulfonyl)-phenyl]-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.27 (brs, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),7.69-7.60 (m, 4H), 7.29 (d, J=6.0 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.34(d, J=6.4 Hz, 2H), 3.13-3.04 (m, 4H), 1.66-1.58 (m, 4H). MS: m/z 360.9(M+H⁺).

Example 228: Synthesis of1-[4-(Piperidine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.33 (brs, 1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.64(d, J=8.8 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 6.99(t, J=5.6 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.88-2.76 (m, 4H), 1.57-1.47(m, 4H), 1.40-1.29 (m, 2H). MS: m/z 375.0 (M+H⁺).

Example 229: Synthesis of1-[4-(Morpholine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.34 (brs, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H), 7.67(d, J=9.2 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.30 (d, J=6.0 Hz, 2H), 6.97(t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.68-3.58 (m, 4H), 2.86-2.76(m, 4H). MS: m/z 377.1 (M+H⁺).

Example 230: Synthesis of1-[4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.34 (brs, 1H), 8.51 (d, J=5.2 Hz, 2H), 7.67 (d,J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.30 (d, J=4.8 Hz, 2H), 6.99 (t,J=5.6 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.92-2.73 (m, 4H), 2.41-2.27 (m,4H), 2.13 (s, 3H). MS: m/z 390.0 (M+H⁺).

Example 231: Synthesis of1-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.23 (s, 1H), 8.48 (d, J=6.0 Hz, 2H), 7.73 (d,J=8.7 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.27-7.24 (m, 6H), 6.93-6.88 (m,1H), 4.52 (s, 4H), 4.32 (d, J=6.3 Hz, 2H). MS: m/z 409.1 (M+H⁺).

Example 232: Synthesis of1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-urea

Step 1: To a solution of 8-oxa-3-aza-bicyclo[3.2.1]octane (100 mg, 0.668mmol, HCl salt) in dry DCM (20 mL) was added 4-nitro-benzenesulfonylchloride (296 mg, 1.34 mmol) and followed by TEA (202.8 mg, 2.00 mmol).The resulting mixture was stirred at room temperature for 2 hours. Thereaction was monitored by TLC. Then the mixture was concentrated invacuum to give a residue which was purified by a silica gel columneluting with DCM/MeOH (60:1) to afford3-(4-nitro-benzenesulfonyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (150 mg,yield: 75%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.39 (dd,J=7.2, 2.0 Hz, 2H), 7.92 (dd, J=6.8, 2.0 Hz, 2H), 4.39 (s, 2H), 3.45 (d,J=11.6 Hz, 2H), 2.27 (dd, J=11.2, 2.0 Hz, 2H), 2.05-1.95 (m, 4H).

Step 2: To a solution of3-(4-nitro-benzenesulfonyl)-8-oxa-3-aza-bicyclo[3.2.1]octane (100 mg,0.335 mmol) in EtOAc (20 mL) was added Pd/C (20 mg, 20% wt). Theresulting suspension was stirred at room temperature overnight. Thereaction was monitored by LC-MS. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenylamine (83 mg,yield: 92%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.32 (d,J=8.8, 2H), 6.64 (d, J=8.8 Hz, 2H), 6.07 (brs, 2H), 4.31 (s, 2H), 3.15(d, J=11.6 Hz, 2H), 2.37 (dd, J=11.6, 2.0 Hz, 2H), 1.82-1.74 (m, 4H).

Step 3: To a solution of4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenylamine (100 mg,0.373 mmol) in DCM (10 mL) was added phenyl carbonchloridate (117 mg,0.745 mmol) and followed by TEA (113 mg, 55.4 mmol). The resultingmixture was stirred at room temperature overnight. The reaction wasmonitored by TLC. Then the mixture was concentrated in vacuum to give aresidue which was purified by silica gel column eluting with DCM/MeOH(60:1) to afford[4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-carbamic acidphenyl ester (132 mg, yield: 92%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ=7.71 (d, J=9.2 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 7.42 (t, J=8.0Hz, 2H), 7.27 (t, J=7.2 Hz, 1H), 7.22-7.18 (m, 2H), 4.36 (s, 2H), 3.38(d, J=11.2 Hz, 2H), 2.63 (dd, J=7.2, 2.0 Hz, 2H), 2.06-1.90 (m, 4H).

Step 4: To a solution of[4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-carbamic acidphenyl ester (120 mg, 0.309 mmol) in dioxane (8 mL) was addedc-Pyridin-3-yl-methylamine (40 mg, 0.371 mmol) and followed by TEA (94mg, 0.927 mmol). The resulting mixture was stirred at 80° C. overnight.The reaction was monitored by LC-MS. Then the white solid precipitatedfrom the reaction mixture was filtered. The cake was washed with dioxane(20 mL) and dried in air to afford1-[4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-urea(76.4 mg, yield: 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.19 (brs, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.71(d, J=8.0 Hz, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.36(dd, J=8.0, 4.8 Hz, 1H), 6.91 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H),4.32 (s, 2H), 3.21 (d, J=10.8 Hz, 2H), 2.40 (d, J=10.0 Hz, 2H),1.84-1.73 (m, 4H). MS: m/z 403.1 (M+H⁺).

Example 233: Synthesis of1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-2-ylmethyl-urea

The title compound was prepared as described in example1-[4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.35 (brs, 1H), 8.53 (d, J=4.0 Hz, 1H),7.78 (dt, J=8.0, 2.0 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz,2H), 7.56 (d, J=8.4 Hz, 2H), 7.35 (d, J=7.6 Hz, 1H), 6.96 (t, J=5.6 Hz,1H), 4.43 (d, J=6.0 Hz, 2H), 4.32 (s, 2H), 3.21 (d, J=10.8 Hz, 2H), 2.41(dd, J=11.2, 2.0 Hz, 2H), 1.83-1.74 (m, 4H). MS: m/z 403.1 (M+H⁺).

Example 234: Synthesis of1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.51 (brs, 1H), 8.74 (d, J=6.0 Hz, 2H),7.73 (d, J=6.4 Hz, 2H), 7.65 (d, J=9.2 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H),7.17 (t, J=5.6 Hz, 1H), 4.52 (d, J=6.4 Hz, 2H), 4.32 (s, 2H), 3.21 (d,J=11.2 Hz, 2H), 2.40 (dd, J=11.2, 2.0 Hz, 2H), 1.84-1.73 (m, 4H). MS:m/z 403.1 (M+H⁺).

Example 235: Synthesis of1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.34 (brs, 1H), 8.49 (dd, J=4.8, 1.2 Hz, 2H),7.72-7.60 (m, 4H), 7.28 (d, J=6.0 Hz, 2H), 7.17-7.08 (m, 4H), 6.98 (t,J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.13 (s, 2H), 3.23 (t, J=6.0 Hz,2H), 2.85 (t, J=6.0 Hz, 2H). MS: m/z 423.0 (M+H⁺).

Example 236: Synthesis of1-[4-(8-Chloro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.27 (s, 1H), 8.50 (d, J=5.2 Hz, 2H), 7.70-7.63(m, 4H), 7.31-7.27 (m, 3H), 7.21 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.9 Hz,1H), 6.94 (t, J=5.2 Hz, 1H), 4.34 (d, J=5.2 Hz, 2H), 4.12 (s, 2H), 3.28(t, J=6.0 Hz, 2H), 2.89 (t, J=5.2 Hz, 2H). MS: m/z 456.9 (M+H⁺).

Example 237: Synthesis ofPyridin-4-ylmethyl-3-[4-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-urea

Step 1: To the solution of 2-(3-trifluoromethyl-phenyl)-ethylamine (1.7g, 9.0 mmol) in DCM (10 mL) was added TEA (1.4 g, 9.9 mmol) at 0° ° C.under N₂. Then a solution of TFAA (2.1 g, 9.9 mmol) in DCM (10 mL) wasadded dropwise. The mixture was stirred at room temperature for 2 hrs.The reaction mixture was diluted with DCM (10 mL), washed with H₂O (10mL), dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column eluting with PE/EtOAc(8:1) to give the2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide (1.3 g,yield: 52%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.476 (brs,1H), 7.59-7.52 (m, 4H), 3.49-3.44 (m, 2H), 2.92 (t, J=6.8 Hz, 2H).

Step 2: (CH₂O)_(n) was added to2,2,2-trifluoro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-acetamide (1.3 g,4.6 mmol) in a 100 mL round-bottomed before a solution of CH₃COOH (15mL) and H₂SO₄ (20 mL) was added. The mixture was stirred at roomtemperature for 2 hrs under N₂. The reaction mixture was extracted withEtOAc (40 mL*2). The combined organic layer was washed with ice water(30 mL) and aq.NaHCO₃, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash (8% EtOAc in PE) to give the2,2,2-trifluoro-1-(8-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone(0.9 g, yield: 64%) as a white solid. MS: m/z 298.4 (M+H⁺).

Step 3: To a solution of2,2,2-trifluoro-1-(8-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone(315 mg, 4.6 mmol) in EtOH (10 mL) was added a solution of NaOH (440 mg,11.0 mmol) in H₂O (10 mL). The mixture was refluxed at 90° ° C. for 2hrs. Then Boc₂O (36 mg, 1.65 mmol) was added and the reaction mixturewas stirred for another 1 h at room temperature. After that, thereaction mixture was concentrated under reduced pressure to dryness andextracted with DCM (20 mL). The organic layer was washed with H₂O (20mL), dried over Na₂SO₄ and concentrated under reduced pressure to givethe 8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (350 mg, yield: quantitative) as a white solid.

Step 4: The mixture of8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (350 mg, 1.1 mol) in TFA/DCM (1.3 g/3 mL) was stirredat room temperature for 1 hrs. The reaction was concentrated to drynessin vacuum to afford 8-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline(400 mg, yield: quantitative) as a white solid.

Step 5: This step is similar to general procedure for4-(3-pyridin-4-ylmethyl-ureido)-N-(3-chloro-phenyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆):δ=9.27 (s, 1H), 8.50 (dd, J=2.8, 1.6 Hz, 2H),7.67-7.63 (m, 4H), 7.56 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.39(t, J=7.9 Hz, 1H), 7.30 (d, J=6.0 Hz, 2H), 6.94 (t, J=6.0 Hz, 1H),4.35-4.30 (m, 4H), 3.37-3.32 (m, 2H), 2.95 (t, J=6.0 Hz, 2H). MS: m/z490.9 (M+H⁺).

Example 238: Synthesis ofPyridin-4-ylmethyl-3-[4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-urea

The title compound was prepared as described in example1-Pyridin-4-ylmethyl-3-[4-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-urea.H NMR (400 MHz, DMSO-d₆): δ=9.28 (s, 1H), 8.50 (dd, J=1.6, 3.2 Hz, 2H),7.69 (d, J=8.8 Hz, 2H), 7.63 (d, J=9.2 Hz, 2H), 7.50 (d, J=6.4 Hz, 2H),7.39 (d, J=8.8 Hz, 1H), 7.28 (d, J=6.0 Hz, 2H), 6.94 (t, J=6.0 Hz, 1H),4.34 (d, J=6.0 Hz, 2H), 4.23 (s, 2H), 3.27 (overlap, 2H), 2.94 (t, J=6.0Hz, 2H). MS: m/z 490.9 (M+H⁺).

Example 239: Synthesis of1-[4-(8-Fluoro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 2-fluoro-benzaldehyde (5.0 g, 40.3 mmol) inMeOH (80 mL) was added 2,2-diethoxy-ethylamine (5.4 g, 40.3 mmol). Themixture was stirred at 70° C. for 2 hrs and at room temperature for 16hrs. Then NaBH₄ (1.5 g, 40.3 mmol) was added portionwise. After stirringat room temperature for 3 hrs, the reaction mixture was diluted with H₂O(50 mL), concentrated to 50 mL and extracted with EtOAc (50 mL*3). Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to give (2,2-diethoxy-ethyl)-(2-fluoro-benzyl)-amine(crude) as colorless oil which was used to the next step without furtherpurification.

Step 2: To a solution of (2,2-diethoxy-ethyl)-(2-fluoro-benzyl)-amine(5.0 g, crude) and pyridine (4.4 g, 56.0 mmol) in DCM (100 mL) was addedTsCl (5.1 g, 27.0 mmol) portion wise at 0° C. After stirring at roomtemperature for 16 hrs, the reaction mixture was washed with aq.HCl (2N,30 mL), sat.NaHCO₃ (30 mL) and brine (30 mL). The DCM solution was driedover Na₂SO₄ and concentrated. The residue was purified by silica gelcolumn eluting with PE/EtOAc (30:1) to giveN-(2,2-diethoxy-ethyl)-N-(2-fluoro-benzyl)-4-methyl-benzenesulfonamide(5.7 g, yield: 71% for two steps) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ=7.67 (d, J=8.4 Hz, 2H), 7.37 (td, J=7.6, 1.2 Hz, 1H),7.28-7.18 (m, 3H), 7.07 (td, J=7.6, 1.2 Hz, 1H), 6.94 (td, J=8.4, 0.8Hz, 1H), 4.59-4.55 (m, 3H), 3.66-3.57 (m, 2H), 3.43-3.34 (m, 2H), 3.27(d, J=5.2 Hz, 2H), 2.42 (s, 3H), 1.11 (t, J=7.2 Hz, 6H).

Step 3: To a stirring solution ofN-(2,2-diethoxy-ethyl)-N-(2-fluoro-benzyl)-4-methyl-benzenesulfonamide(4.4 g, 11.1 mmol) in DCM (100 mL) was added AlCl₃ (5.9 g, 44.4 mmol).After stirring at 45° C. for 1.5 hrs, the reaction mixture was poured toice-water (100 mL) and extracted with DCM (100 mL*2). The combinedorganic layer was washed with sat.NaHCO₃ (100 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column eluting withPE/EtOAc (40:1) to give8-fluoro-2-(toluene-4-sulfonyl)-1,2-dihydro-isoquinoline (880 mg, yield:26%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=7.73 (d, J=8.4 Hz,2H), 7.35-7.27 (m, 2H), 7.10 (dd, J=13.8, 7.8 Hz, 1H), 6.86-6.79 (m,2H), 6.72 (d, J=7.2 Hz, 1H), 5.82 (dd, J=7.8, 1.8 Hz, 1H), 4.68 (s, 2H),2.41 (s, 3H).

Step 4: t-BuOK (1.5 g, 13.2 mmol) was dissolved in t-BuOH (30 mL) andthen 8-fluoro-2-(toluene-4-sulfonyl)-1,2-dihydro-isoquinoline (800 mg,2.6 mmol) was added. After stirring at 85° C. for 1 h, the reactionmixture was poured to water (100 mL) and extracted with EtOAc (50 mL*2).The combined organic layer was washed with brine (30 mL), dried overNa₂SO₄ and concentrated. The residue was purified by silica gel columneluting with PE/EtOAc (30:1) to give 8-fluoro-isoquinoline (230 mg,yield: 59%) as yellow oil. ¹H NMR (400 MHz, CDCl₃): δ=9.55 (s, 1H), 8.60(d, J=5.6 Hz, 1H), 7.68-7.60 (m, 3H), 7.27-7.21 (m, 1H).

Step 5: A mixture of 8-fluoro-isoquinoline (100 mg, 0.7 mmol) and PtO₂(30 mg) in AcOH (4 mL) was stirred at room temperature for 5 hrs underH₂ atmosphere (50 psi). The reaction mixture was filtered to remove thecatalyst. The filtrate was concentrated and co-evaporated with toluene(15 mL*3) to give 8-fluoro-1,2,3,4-tetrahydro-isoquinoline (crude) aspale yellow oil which was used to the next step without furtherpurification.

Step 6: This step was similar to general procedure ofN-(2-methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.28 (s, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.70(d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.28 (d, J=5.2 Hz, 2H), 7.21(dd, J=13.4, 7.8 Hz, 1H), 7.05-6.97 (m, 2H), 6.93 (t, J=5.6 Hz, 1H),4.34 (d, J=5.6 Hz, 2H), 4.13 (s, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.88 (t,J=5.6 Hz, 2H). MS: m/z 440.9 (M+H⁺).

Example 240: Synthesis of1-[4-(8-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: A mixture of 2-methyl-benzaldehyde (5.0 g, 41.7 mmol) and2,2-diethoxy-ethylamine (5.5 g, 41.7 mmol) in toluene (50 mL) wasrefluxed for 3 hrs with a Dean-Stark trap. The reaction mixture wasconcentrated to give (2,2-diethoxy-ethyl)-(2-methyl-benzylidene)-amine(crude) as colorless oil which was used to the next step without furtherpurification.

Step 2&3: To a solution of(2,2-diethoxy-ethyl)-(2-methyl-benzylidene)-amine (crude) in THF (50 mL)was added ethyl chloroformate (4.6 g, 41.7 mmol) at −10° C. Afterstirring at −10° C. for 5 min, the cooling bath was removed and P(OMe)₃(6.6 g, 53.2 mmol) was added at room temperature. The reaction wasstirred at room temperature for 20 hrs and then concentrated to removedtraces of P(OMe)₃. The residue was co-evaporated with toluene (20 mL*2)to give{[(2,2-diethoxy-ethyl)-ethoxycarbonyl-amino]-o-tolyl-methyl}-phosphonicacid dimethyl ester (crude) as colorless oil which was used to the nextstep without further purification.

Step 4: To a solution of{[(2,2-diethoxy-ethyl)-ethoxycarbonyl-amino]-o-tolyl-methyl}-phosphonicacid dimethyl ester (crude) in DCM (60 mL) was added TiCl₄ (27.5 mL, 250mmol). After stirring at 45° C. for 24 hrs, the reaction mixture waspoured to ice (100 g)/NH₄OH (100 mL). The mixture was filtered to removeTiO₂ and the filtrate was washed with aq.HCl (1 N, 50 mL*2). The acidiclayer was washed with DCM (20 mL) and then basified with NH₄OH to adjustpH=9. The suspension was extracted with DCM (50 mL*3). The combinedorganic layer was dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column eluting with PE/EtOAc (10:1) to give8-methyl-isoquinoline (2.0 g, yield: 34% for four steps) as colorlessoil. ¹H NMR (400 MHz, CDCl₃): δ=9.46 (s, 1H), 8.55 (d, J=5.6 Hz, 1H),7.68-7.54 (m, 3H), 7.39 (d, J=6.4 Hz, 1H), 2.79 (s, 3H).

Step 5: A mixture of 8-methyl-isoquinoline (100 mg, 0.7 mmol) and PtO₂(30 mg) in AcOH (3 mL) was stirred at room temperature for 5 hrs underH₂ atmosphere (50 psi). The reaction mixture was filtered to remove thecatalyst. The filtrate was concentrated and co-evaporated with toluene(15 mL*3) to give 8-methyl-1,2,3,4-tetrahydro-isoquinoline (crude) ascolorless oil which was used to the next step without furtherpurification.

Step 6: This step was similar to general procedure ofN-(2-methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.26 (s, 1H), 8.49 (dd, J=4.4, 1.6 Hz, 2H),7.71 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.28 (d, J=5.6 Hz, 2H),7.08-6.91 (m, 4H), 4.34 (d, J=6.0 Hz, 2H), 4.03 (s, 2H), 3.22 (t, J=5.6Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 2.15 (s, 3H). MS: m/z 436.9 (M+H⁺).

Example 241: Synthesis of1-[4-(3-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.17 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.63 (d,J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.32 (d, J=5.6 Hz, 2H), 7.16-7.08(m, 3H), 7.01 (d, J=7.2 Hz, 1H), 6.90 (t, J=6.0 Hz, 1H), 4.99 (q, J=2.8Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.75-3.68 (m, 1H), 3.39 (overlap, 1H),2.64-2.62 (m, 2H), 1.34 (d, J=6.8 Hz, 3H). MS: m/z 436.9 (M+H⁺).

Example 242: Synthesis ofN-Phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): 8.51 (s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.49 (d, J=9.2Hz, 2H), 7.40 (s, 2H), 7.21-7.17 (t, J=8 Hz, 2H), 7.087.04 (m, 3H), 4.43(s, 2H). MS:m/z 382.9 (M+H⁺)

Example 243: Synthesis ofN-(2-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.45 (brs, 1H), 8.49 (dd, J=4.4, 1.6 Hz, 2H),7.58-7.47 (m, 4H), 7.27 (d, J=6.0 Hz, 2H), 7.24-7.16 (m, 2H), 7.09-7.03(m, 1H), 6.91-6.87 (m, 1H), 6.86-6.81 (m, 1H), 4.32 (d, J=6.0 Hz, 2H),3.34 (s, 3H). MS: m/z 412.9 (M+H⁺).

Example 244: Synthesis ofN-(3-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=10.13 (brs, 1H), 9.21 (brs, 1H), 8.49 (d, J=5.6Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 7.27 (d, J=5.6Hz, 2H), 7.11 (t, J=4.0 Hz, 1H), 6.93 (t, J=5.6 Hz, 1H), 6.67-6.62 (m,2H), 6.59-6.54 (m, 1H), 4.32 (d, J=6.0 Hz, 2H), 3.65 (s, 3H). MS: m/z412.9 (M+H⁺).

Example 245: Synthesis ofN-(4-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.72 (brs, 1H), 9.24 (brs, 1H), 8.49 (d, J=5.4 Hz,2H), 7.58-7.46 (m, 4H), 7.27 (d, J=5.1 Hz, 2H), 7.02-6.90 (m, 3H),6.84-6.75 (m, 2H), 4.32 (d, J=5.7 Hz, 2H), 3.66 (s, 3H). MS: m/z 412.9(M+H⁺).

Example 246: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-o-tolyl-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.34 (brs, 1H), 9.26 (brs, 1H), 8.50 (d, J=6.0 Hz,2H), 7.58-7.46 (m, 4H), 7.29 (d, J=5.6 Hz, 2H), 7.15-7.10 (m, 1H),7.10-7.05 (m, 2H), 7.01-6.92 (m, 2H), 4.33 (d, J=5.6 Hz, 2H), 2.00 (s,3H). MS: m/z 396.9 (M+H⁺).

Example 247: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-m-tolyl-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.94 (brs, 1H), 9.32 (brs, 1H), 8.48 (d, J=4.8 Hz,2H), 7.61 (d, J=8.7 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 7.30-7.23 (m, 2H),7.12-7.01 (m, 2H), 6.91-6.84 (m, 2H), 6.80 (d, J=7.5 Hz, 1H), 4.31 (d,J=5.7 Hz, 2H), 1.84 (s, 3H). MS: m/z 396.9 (M+H⁺).

Example 248: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-p-tolyl-benzenesulfonamide

The title compound was prepared as described in exampleN-cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d₆): δ=9.93 (brs, 1H), 9.19 (brs, 1H), 8.49 (d, J=4.8 Hz,2H), 7.57 (d, J=8.7 Hz, 2H), 7.50 (d, J=9.3 Hz, 2H), 7.30-7.24 (m, 2H),7.04-6.98 (m, 2H), 6.97-6.88 (m, 3H), 4.32 (d, J=5.4 Hz, 2H), 2.18 (s,3H). MS: m/z 397.0 (M+H⁺).

Example 249: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide

Triphosgen (70 mg, 0.235 mmol) was dissolved in DCM (10 mL) and cooledto −10° C. under N₂ atmosphere. To this cooled solution was addeddropwise a mixture of 4-amino-N-thiazol-2-yl-benzenesulfonamide (200 mg,0.783 mmol) and TEA (238 mg, 2.35 mmol) in DCM (10 mL). The mixture wasstirred at −10° C. for 5 min and allowed to warm up to room temperaturefor 1 hour. Then a solution of c-pyridin-4-yl-methylamine (85 mg, 0.861mmol) and TEA (238 mg, 2.35 mmol) in DCM (10 mL) was added. Theresulting mixture was stirred at room temperature for 16 hours. Thereaction was monitored by LC-MS. Then the mixture was diluted with DCM(20 mL) and washed with brine (20 mL). The organic layer wasconcentrated in vacuum to give a residue which was purified by prep-HPLCwith NH₄Ac as additive to afford4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide (151.6mg, yield: 50%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.17(brs, 1H), 8.49 (dd, J=4.8, 1.6 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.47(d, J=8.8 Hz, 2H), 7.28 (d, J=5.6 Hz, 2H), 7.09 (d, J=4.0 Hz, 1H), 7.05(t, J=6.0 Hz, 1H), 6.62 (d, J=4.4 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H). MS:m/z 389.9 (M+H⁺).

Example 250: Synthesis ofN-(4,5-Dimethyl-oxazol-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=9.32 (brs, 1H), 8.51 (dd, J=4.8, 1.6 Hz, 2H),7.65-7.54 (m, 4H), 7.30 (d, J=6.0 Hz, 2H), 7.01 (t, J=5.6 Hz, 1H), 4.34(d, J=6.0 Hz, 2H), 2.04 (s, 3H), 1.61 (s, 3H). MS: m/z 402.0 (M+H⁺).

Example 251: Synthesis ofN-(5-Methyl-isoxazol-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=9.24 (brs, 1H), 8.49 (d, J=6.0 Hz, 2H), 7.64(d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.28 (d, J=6.0 Hz, 2H), 7.02(t, J=6.4 Hz, 1H), 5.99 (s, 1H), 4.33 (d, J=6.0 Hz, 2H), 2.22 (s, 3H).MS: m/z 387.9 (M+H⁺).

Example 252: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrimidin-2-yl-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=9.30 (brs, 1H), 8.49 (dd, J=4.8, 1.6 Hz, 2H),8.39 (d, J=4.4 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H),7.28 (d, J=5.6 Hz, 2H), 7.08 (t, J=6.0 Hz, 1H), 6.86 (s, 1H), 4.33 (d,J=6.4 Hz, 2H). MS: m/z 384.9 (M+H⁺).

Example 253: Synthesis ofN-(4-Methyl-pyrimidin-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 2H),8.22 (d, J=4.8 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H),7.28 (d, J=6.0 Hz, 2H), 7.09 (t, J=5.6 Hz, 1H), 6.76 (d, J=4.4 Hz, 1H),4.33 (d, J=5.6 Hz, 2H), 2.26 (s, 3H). MS: m/z 398.9 (M+H⁺).

Example 254: Synthesis ofN-Pyridin-2-yl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=11.55 (brs, 1H), 9.14 (brs, 1H), 8.49 (d,J=2.0 Hz, 2H), 8.04 (d, J=4.8 Hz, 1H), 7.74 (d, J=9.2 Hz, 2H), 7.71-7.65(m, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.27 (d, J=5.2 Hz, 2H), 7.11 (d, J=8.4Hz, 1H), 6.93-6.84 (m, 2H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 383.9(M+H⁺).

Example 255: Synthesis of4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-N-pyridin-2-yl-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=12.52 (brs, 1H), 9.04 (brs, 1H), 8.04 (d,J=4.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.70-7.64 (m, 1H), 7.59-7.44 (m,4H), 7.10 (d, J=8.8 Hz, 1H), 6.87 (t, J=6.4 Hz, 1H), 6.61 (t, J=5.6 Hz,1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 372.9 (M+H⁺).

Example 256: Synthesis ofN-Benzyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide. ¹HNMR (400 MHz, DMSO-d₆): δ=12.64 (brs, 1H), 9.05 (s, 1H), 7.90 (s, 1H),7.70-7.42 (m, 6H), 7.33-7.19 (m, 5H), 6.68 (t, J=5.2 Hz, 1H), 4.16 (d,J=5.2 Hz, 2H), 3.92 (s, 2H). MS: m/z 385.9 (M+H⁺).

Example 257: Synthesis of1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a solution of 1,2,3,4-tetrahydro-isoquinoline (266.4 mg, 2.0mmol) in dry DCM (20 mL) was added 4-nitro-benzenesulfonyl chloride (665mg, 3.0 mmol) and followed by TEA (607.2 mg, 6.0 mmol). The resultingmixture was stirred at room temperature for 1 hour. The reaction wasmonitored by TLC. Then the mixture was concentrated in vacuum to give aresidue which was purified by silica gel column (DCM as eluent) toafford 2-(4-nitro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline (612mg, yield: 96%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.42(dd, J=6.8, 2.0 Hz, 2H), 8.10 (dd, J=6.8, 2.0 Hz, 2H), 7.19-7.18 (m,4H), 4.29 (s, 2H), 3.40 (t, J=6.4 Hz, 2H), 2.86 (d, J=6.0 Hz, 2H).

Step 2: To a solution of2-(4-nitro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline (612 mg,1.92 mmol) in MeOH (20 mL) was added Pd/C (122 mg, 20% wt). Theresulting suspension was stirred at room temperature overnight. Thereaction was monitored by LC-MS. Then Pd/C was filtered off and thefiltrate was concentrated in vacuum to afford4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenylamine (510 mg, yield:92%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.44 (dd, J=7.2, 1.6Hz, 2H), 7.17-7.08 (m, 4H), 6.64 (dd, J=6.8, 2.0 Hz, 2H), 6.08 (s, 2H),4.06 (s, 2H), 3.16 (t, J=6.0 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H).

Step 3: To a solution of4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenylamine (144 mg, 0.50mmol) in DCM (20 mL) was added phenyl carbonchloridate (94 mg, 0.60mmol) and followed by TEA (152 mg, 1.50 mmol). The resulting mixture wasstirred at room temperature for 1 hour. The reaction was monitored byTLC. Then the mixture was concentrated in vacuum to give a residue whichwas purified by silica gel column eluting with PE/EtOAc (10:1 to 4:1) toafford [4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-carbamic acidphenyl ester (176 mg, yield: 86%) as a white solid.

Step 4: To a solution of[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-carbamic acid phenylester (100 mg, 0.245 mmol) in ACN (20 mL) was addedc-(1H-pyrazol-4-yl)-methylamine (100 mg, 80% purity) and followed by TEA(74.4 mg, 0.735 mmol). The resulting mixture was stirred at 80° C. for 3hours. The reaction was monitored by LC-MS. Then the mixture wasconcentrated in vacuum to give a residue which was purified by prep-HPLCwith NH₄OH as additive to afford1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(50.0 mg, yield: 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=12.66 (brs, 1H), 9.04 (brs, 1H), 7.74-7.55 (m, 5H), 7.44 (brs, 1H),7.20-7.06 (m, 4H), 6.58 (t, J=5.2 Hz, 1H), 4.16 (d, J=5.6 Hz, 2H), 4.13(s, 2H), 3.23 (t, J=5.6 Hz, 2H), 2.84 (t, J=6.0 Hz, 2H). MS: m/z 412.0(M+H⁺).

Example 258: Synthesis of1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.65 (brs, 1H), 9.00 (s, 1H), 7.62 (d,J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.45 (brs, 1H), 6.56 (t, J=5.2Hz, 1H), 4.32 (s, 2H), 4.17 (d, J=5.6 Hz, 2H), 3.21 (d, J=10.8 Hz, 2H),2.41 (dd, J=11.2, 1.6 Hz, 2H), 1.85-1.72 (m, 4H). MS: m/z 391.9 (M+H⁺).

Example 259: Synthesis ofN-Cyclobutylmethyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.58 (brs, 1H), 8.86 (s, 1H), 7.67-7.46(m, 6H), 7.34 (t, J=6.0 Hz, 1H), 6.51 (d, J=5.2 Hz, 1H), 4.16 (d, J=5.6Hz, 2H), 2.70 (t, J=6.8 Hz, 2H), 2.35-2.25 (m, 1H), 1.94-1.84 (m, 2H),1.80-1.68 (m, 2H), 1.62-1.52 (m, 2H). MS: m/z 364.0 (M+H⁺).

Example 260: Synthesis ofN-Phenyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.66 (brs, 1H), 8.88 (s, 1H), 7.66-7.42(m, 6H), 7.18 (t, J=7.6 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 6.95 (t, J=7.2Hz, 1H), 6.54 (t, J=5.2 Hz, 1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 371.9(M+H⁺).

Example 261: Synthesis of1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.65 (brs, 1H), 9.00 (s, 1H), 7.62 (d,J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.45 (brs, 1H), 6.56 (t, J=5.2Hz, 1H), 4.32 (s, 2H), 4.17 (d, J=5.6 Hz, 2H), 3.21 (d, J=10.8 Hz, 2H),2.41 (dd, J=11.2, 1.6 Hz, 2H), 1.85-1.72 (m, 4H). MS: m/z 391.9 (M+H⁺).

Example 262: Synthesis of4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-N-pyridin-2-yl-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.52 (brs, 1H), 9.04 (brs, 1H), 8.04 (d,J=4.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.70-7.64 (m, 1H), 7.59-7.44 (m,4H), 7.10 (d, J=8.8 Hz, 1H), 6.87 (t, J=6.4 Hz, 1H), 6.61 (t, J=5.6 Hz,1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 372.9 (M+H⁺).

Example 263: Synthesis ofN-Phenyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.66 (brs, 1H), 8.88 (s, 1H), 7.66-7.42(m, 6H), 7.18 (t, J=7.6 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 6.95 (t, J=7.2Hz, 1H), 6.54 (t, J=5.2 Hz, 1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 371.9(M+H⁺).

Example 264: Synthesis ofN-Benzyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (brs, 1H), 9.05 (s, 1H), 7.90 (s,1H), 7.70-7.42 (m, 6H), 7.33-7.19 (m, 5H), 6.68 (t, J=5.2 Hz, 1H), 4.16(d, J=5.2 Hz, 2H), 3.92 (s, 2H). MS: m/z 385.9 (M+H⁺).

Example 265: Synthesis ofN-Cyclobutylmethyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.58 (brs, 1H), 8.86 (s, 1H), 7.67-7.46(m, 6H), 7.34 (t, J=6.0 Hz, 1H), 6.51 (d, J=5.2 Hz, 1H), 4.16 (d, J=5.6Hz, 2H), 2.70 (t, J=6.8 Hz, 2H), 2.35-2.25 (m, 1H), 1.94-1.84 (m, 2H),1.80-1.68 (m, 2H), 1.62-1.52 (m, 2H). MS: m/z 364.0 (M+H⁺).

Example 266: Synthesis ofN-Cyclopentyl-N-methyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (brs, 1H), 8.92 (s, 1H), 7.67-7.46(m, 6H), 6.52 (t, J=5.6 Hz, 1H), 4.22-4.10 (m, 3H), 2.59 (s, 3H),1.55-1.44 (m, 4H), 1.43-1.34 (m, 2H), 1.32-1.25 (m, 2H). MS: m/z 378.0(M+H⁺).

Example 267: Synthesis ofN-Benzyl-N-isopropyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.09 (s, 1H), 8.29 (s, 1H), 7.70 (d, J=8.0Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.41 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2Hz, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.02 (s, 1H), 6.82 (t, J=5.6 Hz, 1H),4.39 (d, J=6.4 Hz, 2H), 4.34 (s, 2H), 4.06-3.96 (m, 1H), 0.83 (d, J=6.4Hz, 6H). MS: m/z 429.0 (M+H⁺).

Example 268: Synthesis ofN-Benzyl-N-isopropyl-4-(3-thiazol-5-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.14 (s, 1H), 8.98 (s, 1H), 7.91-7.54 (m,5H), 7.50-7.17 (m, 5H), 7.03-6.28 (m, 1H), 4.68-4.46 (m, 2H), 4.35 (s,2H), 4.12-3.91 (m, 1H), 0.99-0.62 (m, 6H). MS: m/z 444.9 (M+H⁺).

Example 269: Synthesis ofN-Benzyl-N-isopropyl-4-(3-thiazol-2-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.32 (s, 1H), 7.79-7.69 (m, 3H), 7.68-7.60(m, 3H), 7.42 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.25 (t, J=7.2Hz, 1H), 7.15 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 4.35 (s, 2H),4.08-3.97 (m, 1H), 0.84 (d, J=6.4 Hz, 6H). MS: m/z 444.9 (M+H⁺).

Example 270: Synthesis ofN-Benzyl-N-isopropyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (brs, 1H), 8.93 (s, 1H), 7.69 (dd,J=6.8, 1.6 Hz, 2H), 7.63-7.49 (m, 4H), 7.41 (d, J=6.8 Hz, 2H), 7.33 (t,J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.53 (t, J=5.2 Hz, 1H), 4.34 (s,2H), 4.17 (d, J=5.2 Hz, 2H), 4.05-3.96 (m, 1H), 0.83 (d, J=6.8 Hz, 6H).MS: m/z 428.0 (M+H⁺).

Example 271: Synthesis of1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.12 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=8.8Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.17-7.08 (m, 4H), 7.01 (s, 1H), 6.82(t, J=5.6 Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.14 (s, 2H), 3.24 (t, J=6.4Hz, 2H), 2.84 (t, J=5.6 Hz, 2H). MS: m/z 412.9 (M+H⁺).

Example 272: Synthesis ofN-(3-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (brs, 1H), 8.86 (s, 1H), 7.89 (t,J=6.4 Hz, 1H), 7.67-7.48 (m, 6H), 7.21-7.15 (m, 1H), 6.83-6.75 (m, 3H),6.50 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.2 Hz, 2H), 3.91 (d, J=6.4 Hz, 2H),3.69 (s, 3H). MS: m/z 415.9 (M+H⁺).

Example 273: Synthesis ofN-(2-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (brs, 1H), 8.89 (s, 1H), 7.98 (t,J=6.0 Hz, 1H), 7.71-7.48 (m, 6H), 7.46-7.36 (m, 2H), 7.33-7.24 (m, 2H),6.52 (t, J=5.6 Hz, 1H), 4.17 (d, J=5.6 Hz, 2H), 4.01 (d, J=6.4 Hz, 2H).MS: m/z 419.9 (M+H⁺).

Example 274: Synthesis ofN-(2-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 8.86 (s, 1H), 7.70 (t,J=6.4 Hz, 1H), 7.67-7.49 (m, 6H), 7.27-7.18 (m, 2H), 6.93-6.85 (m, 2H),6.51 (t, J=5.6 Hz, 1H), 4.17 (d, J=5.6 Hz, 2H), 3.89 (d, J=5.6 Hz, 2H),3.70 (s, 3H). MS: m/z 415.9 (M+H⁺).

Example 275: Synthesis ofN-(4-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.56 (brs, 1H), 8.87 (s, 1H), 7.80 (t,J=6.4 Hz, 1H), 7.68-7.48 (m, 6H), 7.14 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4Hz, 2H), 6.51 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.6 Hz, 2H), 3.85 (d, J=6.0Hz, 2H), 3.71 (s, 3H). MS: m/z 415.9 (M+H⁺).

Example 276: Synthesis ofN-(4-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared as described in example1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.59 (brs, 1H), 8.88 (s, 1H), 7.99 (t,J=6.4 Hz, 1H), 7.67-7.46 (m, 6H), 7.34-7.25 (m, 3H), 7.20 (d, J=7.2 Hz,1H), 6.51 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.6 Hz, 2H), 3.96 (d, J=6.4 Hz,2H). MS: m/z 419.9 (M+H⁺).

Example 277: Synthesis ofN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

Step 1: A mixture of 3-aminobenzenesulfonic acid (34.6 g, 200 mmol),phenyl carbonochoridate (35 g, 220 mmol) and TEA (41 g, 400 mmol) in DCM(500 mL) was stirred at room temperature for 2 hrs. The mixture wasconcentrated in vacuum to remove most of DCM and then filtered. Thefilter cake was dried in vacuum to give the crude product (82 g,>100%),which was used in next step without further purification.

Step 2: A mixture of 3-((phenoxycarbonyl)amino)benzenesulfonic acid (41g, 200 mmol), pyridin-4-ylmethanamine (35 g, 220 mmol) and TEA (41 g,400 mmol) in dioxane (500 mL) was stirred at room temperature for 12hrs. The mixture was concentrated in vacuum. The residue was purified bycolumn chromatography on silica gel eluting with DMC/MeH (10:1) to giveproduct as a yellow solid.

Step 3: A mixture of 3-(3-(pyridin-3-ylmethyl)ureido)benzenesulfonicacid (200 mg, 065 mmol), (COCl)₂ (100 mg, 0.78 mmol) and DMF in DCM (5mL) was stirred at room temperature for 30 minutes. The mixture wasconcentrated in vacuum. The residue was added to a mixture ofcyclopentanamine (70 mg, 0.78 mmol) and TEA (140 mg, 1.3 mmol) in DCM (5mL) at room temperature. The mixture was stirred at room temperature for12 hours and concentrated in vacuum. The residue was purified bypre-HPLC to give the title product (40 mg, 24) as a white solid. ¹H NMR(400 MHz, CD₃OD): δ=8.47 (s, 2H), 8.01 (s, 1H), 7.57-7.55 (m, 1H),7.47-7.391 (m, 4H), 4.46 (s, 2H), 3.53-3.51 (m, 1H), 1.69-1.44 (m, 8H).MS: m/z 375.0 (M+H⁺).

Example 278: Synthesis ofN-benzyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.47-8.46 (s, 2H), 7.98 (s, 1H), 7.56-7.54 (m, 1H),7.42-7.40 (m, 4H), 7.21 (m, 5H) 4.46 (s, 2H), 4.05 (s, 2H). MS: m/z397.0 (M+H⁺).

Example 279: Synthesis of1-(3-(morpholinosulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared as described in exampleN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.47-8.46 (m, 2H), 7.99-7.98 (s, 1H), 7.61-7.58 (m,1H), 7.49-7.40 (m, 1H), 7.39-7.35 (m, 3H), 4.46 (s, 2H), 3.69-3.67 (m,4H), 2.98-2.95 (m, 4H). MS: m/z 377.0 (M+H⁺).

Example 280: Synthesis ofN-(cyclobutylmethyl)-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.47-8.46 (m, 2H), 7.99 (s, 1H), 7.56 (s, 1H),7.44-7.39 (m, 4H), 4.46 (s, 2H), 2.87-2.85 (m, 2H), 2.40-2.36 (m, 1H),1.98-1.29 (m, 6H). MS: m/z 377.0 (M+H⁺).

Example 281: Synthesis ofN-phenethyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide

The title compound was prepared as described in exampleN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide. ¹H NMR(400 MHz, CD₃OD): δ=8.47-8.46 (s, 2H), 7.98 (s, 1H), 7.56-7.54 (m, 1H),7.42-7.39 (m, 4H), 7.223-7.09 (m, 5H), 4.46 (s, 2H), 3.10-3.07 (m, 2H),2.72-2.69 (m, 2H). MS: m/z 411.0 (M+H⁺).

Example 282: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide

Step 1: To a solution of 4-nitro-benzenesulfonyl chloride (2.1 g, 9.5mmol) in Pyr (15 mL) was added 2-chloro-phenylamine (1.0 g, 7.9 mmol)and then was stirred at room temperature for 2 hrs. The reaction wasconcentrated under reduced pressure and the residue was purified bysilica gel column eluting with PE/EtOAc (5:1) to giveN-(2-chloro-phenyl)-4-nitro-benzenesulfonamide (0.8 g, yield: 28%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=10.46 (s, 1H), 8.40 (d, J=8.8Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.32-7.24 (m,3H).

Step 2: To a solution of N-(2-chloro-phenyl)-4-nitro-benzenesulfonamide(320 mg, 1.1 mmol) and Fe (616 mg, 11.0 mmol) in MeOH (5 mL) was asolution of NH₄Cl (1.2 g, 22.0 mmol) in water (10 mL). The reaction wasstirred at 80° C. for 4 hrs. Then the reaction mixture was filtered. Thefiltrate was added to water (10 ml) and then extracted with EtOAc (20mL*2). The combined organic layer was washed with brine (40 mL), driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by silica gel column eluting with PE/EtOAc (2:1) to give4-amino-N-(2-chloro-phenyl)-benzenesulfonamide (305 mg, yield: 98%) as awhite solid.

Step 3 & 4: Step 3 to Step 4 was prepared as described in example1-(4-benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea. ¹H NMR (300 MHz,DMSO-d₆): δ=9.69 (s, 1H), 9.19 (s, 1H), 8.51-8.49 (m, 2H), 7.58-7.54 (m,4H), 7.40-7.34 (m, 1H), 7.29-7.25 (m, 4H), 7.20-7.17 (m, 1H), 6.92 (brs,1H), 4.34-4.32 (m, 2H), MS: m/z 416.9 (M+H⁺).

Example 283: Synthesis of4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-chloro-phenyl)-benzenesulfonamide

The title compound was prepared as described in example4-(3-benzyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide. ¹H NMR (300MHz, DMSO-d₆): δ=10.39 (s, 1H), 9.21 (s, 1H), 8.48 (d, J=5.7 Hz, 2H),7.65-7.53 (m, 4H), 7.28-7.22 (m, 3H), 7.10-7.03 (m, 3H), 6.93 (t, J=1.2Hz, 1H), 4.32 (d, J=2.1 Hz, 2H), MS: m/z 416.9 (M+H⁺).

Example 284: Synthesis of4-(3-pyridin-4-ylmethyl-ureido)-N-(4-chloro-phenyl)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=10.26 (s, 1H), 9.19 (s, 1H), 8.49 (d, J=6.0Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.28-7.25 (m,4H), 7.07 (d, J=8.8 Hz, 2H), 6.93 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz,2H). MS: m/z 416.9 (M+H⁺).

Example 285: Synthesis ofN-Benzyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamide

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆):δ=9.05 (s, 1H), 8.29 (s, 1H), 7.92 (t, J=6.0Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.28-7.22 (m,5H), 7.02 (s, 1H), 6.81 (t, J=5.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 3.92(d, J=6.4 Hz, 2H). MS: m/z 386.9 (M+H⁺).

Example 286: Synthesis of1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-thiazol-5-ylmethyl-urea

The title compound was prepared as described in example4-(3-pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆):δ=9.17 (s, 1H), 8.96 (s, 1H), 7.78 (s, 1H),7.68 (d, J=9.2 Hz, 2H), 7.63 (d, J=9.2 Hz, 2H), 7.13-7.11 (m, 4H), 6.94(t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.14 (s, 2H), 3.24 (t, J=6.0Hz, 2H), 2.84 (t, J=5.6 Hz, 2H). MS: m/z 428.9 (M+H⁺).

Example 287: Synthesis of1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-urea

Step 1: To a solution of4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenylamine (300 mg, 1.04mmoL) and Et₃N (0.3 mL, 2.1 mmoL) in DCM (10 mL) was added phenylchroloformate (290 mg, 1.85 mmoL) at 0° C. and stirred at roomtemperature for 2 hrs.

The reaction mixture was concentrated to dryness in vacuum and theresidue was purified by silica gel column eluting with PE/EtOAc (6:1) togive [4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-carbamic acidphenyl ester (370 mg, yield: 87%) as a white solid. MS: m/z 409.1(M+H⁺).

Step 2: To a solution of[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-carbamic acid phenylester (370 mg, 0.9 mmoL), C-(3,5-dimethyl-isoxazol-4-yl)-methylamine(115 mg, 0.9 mmoL) and Et₃N (0.3 mL, 2.1 mmoL) in MeCN (12 mL) at roomtemperature and stirred for 1 h at 80° C. The reaction mixture wasconcentrated to dryness in vacuum and part of the residue (260 mg) waspurified by Prep-HPLC to give1-[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-urea(41 mg, yield: 10%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ=8.95(s, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.15-7.11 (m,4H), 6.67 (t, J=5.7 Hz, 1H), 4.13 (s, 2H), 4.05 (d, J=5.1 Hz, 2H), 3.23(t, J=5.7 Hz, 2H), 2.84 (t, J=4.8 Hz, 2H), 2.37 (s, 3H), 2.20 (s, 3H).MS: m/z 441.0 (M+H⁺).

Example 288: Synthesis of1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3-chloro-benzenethiol (433.86 mg, 3.0 mmol) inDMF (20 mL) was added 1-chloro-4-nitro-benzene (709 mg, 4.5 mmol) andfollowed by K₂CO₃ (1.24 g, 9.0 mmol). The resulting mixture was stirredat 80° C. overnight. The reaction was monitored by TLC. Then the mixturewas diluted with H₂O (40 mL) and extracted with DCM (20 mL×2). Thecombined organic layers were concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=100:1) to afford4-(3-chlorophenylthio)-1-nitrobenzene (726 mg, yield: 91%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=8.11 (dd, J=6.8, 2.0 Hz, 2H), 7.51 (t,J=1.6 Hz, 1H), 7.44-7.36 (m, 3H), 7.25 (dd, J=6.8, 2.0 Hz, 2H).

Step 2: To a solution of 4-(3-chlorophenylthio)-1-nitrobenzene (726 mg,2.73 mmol) in DCM (40 mL) was added 3-chloro-benzenecarboperoxoic acid(2.02 g, 8.20 mmol, 30% H₂O contained). The resulting mixture wasstirred at room temperature overnight. The reaction was monitored byTLC. Then the mixture was mixed with saturated Na₂SO₃ (30 mL), andextracted with DCM (20 mL×2). The combined organic layers wereconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=10:1) to afford4-[(3-chlorophenyl)sulfonyl]-1-nitrobenzene (705 mg, yield: 88%) asyellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.36 (dd, J=9.2, 2.0 Hz, 2H),8.14 (dd, J=8.8, 2.0 Hz, 2H), 7.95 (t, J=1.6 Hz, 1H), 7.86 (dd, J=8.0,0.8 Hz, 1H), 7.62-7.58 (m, 1H), 7.50 (t, J=8.0 Hz, 1H).

Step 3: To a solution of 4-[(3-chlorophenyl)sulfonyl]-1-nitrobenzene(705 mg, 2.40 mmol) in EtOH/H₂O (v/v=40 mL/10 mL) was added powder iron(673 mg, 12.0 mmol), followed by NH₄Cl (643 mg, 12.0 mmol). Theresulting mixture was stirred at 80° C. overnight. The reaction wasmonitored by LC-MS. Then powder iron was filtered off, and the filtratewas concentrated in vacuum to give a residue, which was purified by areverse-phase column (5˜95% ACN in H₂O) to afford4-(3-chloro-benzenesulfonyl)-phenylamine (586 mg, yield: 92%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.84 (t, J=2.0 Hz, 1H), 7.81-7.77(m, 1H), 7.72-7.66 (m, 1H), 7.63-7.55 (m, 3H), 6.66-6.60 (m, 2H), 6.24(s, 2H).

Step 4: To a solution of 4-(3-chloro-benzenesulfonyl)-phenylamine (586mg, 2.19 mmol) in DCM (40 mL) was added phenyl carbonchloridate (514 mg,3.28 mmol), followed by TEA (664.5 mg, 6.57 mmol). The resulting mixturewas stirred at room temperature for 1 hour. The reaction was monitoredby TLC. Then the mixture was concentrated in vacuum to give a residue,which was purified by a silica gel column eluting with PE/EA=10/1 to 4/1to afford [4-(3-chloro-benzenesulfonyl)-phenyl]-carbamic acid phenylester (662 mg, yield: 78%) as a white solid.

Step 5: To a solution of [4-(3-Chloro-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (200 mg, 0.516 mmol) in ACN (40 mL) was addedc-pyridin-4-yl-methylamine (67 mg, 0.619 mmol), followed by TEA (156 mg,1.548 mmol). The resulting mixture was stirred at 80° C. for 2 hours.The reaction was monitored by LC-MS. Then the mixture was concentratedin vacuum to give a residue, which was purified by a prep-HPLC withNH₄OH as additive to afford1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (88.4mg, yield: 43%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.33 (s,1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.93 (t, J=2.0 Hz, 1H), 7.89-7.83 (m,3H), 7.76-7.72 (m, 1H), 7.67-7.60 (m, 3H), 7.28 (d, J=5.6 Hz, 2H), 6.96(d, J=6.4 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 289: Synthesis of1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.32 (s, 1H), 8.49 (dd, J=4.4, 1.6 Hz, 2H),7.90 (dd, J=6.4, 2.0 Hz, 2H), 7.81 (dd, J=7.2, 1.6 Hz, 2H), 7.71-7.59(m, 4H), 7.27 (dd, J=4.4, 1.6 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.33 (d,J=5.6 Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 290: Synthesis of1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.34 (s, 1H), 8.50 (dd, J=4.4, 1.2 Hz, 2H),8.23 (dd, J=8.0, 2.0 Hz, 1H), 7.78 (dd, J=7.2, 2.0 Hz, 2H), 7.73-7.59(m, 5H), 7.28 (d, J=2.0 Hz, 2H), 6.96 (t, J=5.6 Hz, 1H), 4.34 (d, J=6.4Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 291: Synthesis of1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.04 (s, 1H), 7.93 (t, J=2.0Hz, 1H), 7.90-7.82 (m, 3H), 7.77-7.71 (m, 1H), 7.67-7.59 (m, 3H),7.58-7.45 (m, 2H), 6.57 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.2 Hz, 2H). MS:m/z 390.9 (M+H⁺).

Example 292: Synthesis of1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.04 (s, 1H), 8.23 (dd,J=7.6, 1.6 Hz, 1H), 7.79-7.74 (m, 2H), 7.72-7.63 (m, 2H), 7.63-7.46 (m,5H), 6.56 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.2 Hz, 2H). MS: m/z 390.9(M+H⁺).

Example 293: Synthesis of1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.61 (brs, 1H), 9.04 (s, 1H), 7.90 (dd,J=6.4, 2.0 Hz, 2H), 7.80 (dd, J=7.2, 2.0 Hz, 2H), 7.66 (dd, J=6.4, 2.0Hz, 2H), 7.60 (dd, J=7.2, 2.0 Hz, 2H), 7.57-7.48 (m, 2H), 6.57 (t, J=5.2Hz, 1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 390.9 (M+H⁺).

Example 294: Synthesis of1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.50 (dd, J=5.6, 1.6 Hz, 2H),7.96 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.68-7.55 (m, 3H),7.28 (d, J=6.0 Hz, 2H), 7.20-7.11 (m, 2H), 6.93 (t, J=6.0 Hz, 1H), 4.34(d, J=6.0 Hz, 2H), 3.75 (s, 3H). MS: m/z 397.9 (M+H⁺).

Example 295: Synthesis of1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.30 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),7.82 (dd, J=6.8, 2.0 Hz, 2H), 7.62 (dd, J=7.2, 2.0 Hz, 2H), 7.51 (t,J=8.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.37 (t, J=2.0 Hz, 1H), 7.28 (dd,J=4.4, 1.6 Hz, 2H), 7.24-7.19 (m, 1H), 6.95 (t, J=6.0 Hz, 1H), 4.33 (d,J=5.6 Hz, 2H), 3.82 (s, 3H). MS: m/z 397.9 (M+H⁺).

Example 296: Synthesis of1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d6): δ=12.59 (brs, 1H), 8.94 (s, 1H), 7.95 (dd,J=8.0, 2.0 Hz, 1H), 7.96 (dd, J=6.8, 1.6 Hz, 2H), 7.66-7.60 (m, 1H),7.59-7.44 (m, 4H), 7.19-7.11 (m, 2H), 6.52 (t, J=5.6 Hz, 1H), 4.15 (d,J=5.2 Hz, 2H), 3.74 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 297: Synthesis of1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 8.99 (s, 1H), 7.81 (dd,J=7.2, 1.6 Hz, 2H), 7.64-7.48 (m, 5H), 7.47-7.42 (m, 1H), 7.39-7.35 (m,1H), 7.24-7.18 (m, 1H), 6.54 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H),3.82 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 298: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.16 (brs, 1H), 8.27 (s, 1H), 7.89 (d, J=8.0Hz, 2H), 81 (d, J=8.0 Hz, 2H), 7.70-7.55 (m, 5H), 7.00 (s, 1H), 6.83 (t,J=5.2 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 357.9 (M+H⁺).

Example 299: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.60 (brs, 1H), 8.99 (s, 1H), 7.89 (dd,J=7.2, 1.6 Hz, 2H), 7.79 (dd, J=7.2, 1.6 Hz, 2H), 7.68-7.63 (m, 1H),7.62-7.46 (m, 6H), 6.54 (t, J=5.6 Hz, 1H), 4.14 (d, J=5.6 Hz, 2H). MS:m/z 356.9 (M+H⁺).

Example 300: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 1-benzenesulfonyl-4-nitro-benzene (0.92 g, 3.5mmol) in MeOH/DCM (10 ml/10 ml) was added Pd/C (50% w/w, 0.31 g). Thereaction was stirred at room temperature under H₂ overnight. Then thereaction mixture was filtered. The filtrate was concentrated to give4-benzenesulfonyl-phenylamine (0.84 g, yield: quantitative) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=7.88 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 7.51-7.43 (m, 3H), 6.65 (d, J=8.8 Hz, 2H), 4.14 (s, 2H).

Step 2: The solution of 4-benzenesulfonyl-phenylamine (300 mg, 1.3 mmol)and TEA (0.2 mL, 1.7 mmol) in DCM (20 mL) was degassed and purged withN₂. The mixture was stirred at 0° C. for a while. Then phenylchroloformate (250 mg, 1.6 mmol) was added and the mixture was stirredat room temperature for overnight. After that, the solution wasconcentrated under reduced pressure. The residue was purified by silicagel column (PE/EA=3/1) to give the (4-benzenesulfonyl-phenyl)-carbamicacid phenyl ester (340 mg, 74%) as a white solid.

Step 3: To a solution of (4-benzenesulfonyl-phenyl)-carbamic acid phenylester (200 mg, 0.57 mmol) in MeCN (5 mL) was added DMAP (83 mg, 0.68mmol) and 2-(aminomethyl)pyridine (62 mg, 0.57 mmol). The mixture wasrefluxed at 80° C. for overnight. After that, the solution wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 1-(4-benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea(24.7 mg, yield: 11%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆):δ=9.30 (s, 1H), 8.49 (d, J=6.0 Hz, 2H), 7.89 (d, J=6.9 Hz, 2H), 7.81 (d,J=8.7 Hz, 2H), 7.66-7.57 (m, 5H), 7.27 (d, J=5.7 Hz, 2H), 6.93 (t, J=5.1Hz, 1H), 4.33 (d, J=6.4 Hz, 2H). MS: m/z 367.9 (M+H⁺).

Example 301: Synthesis of1-(4-Phenylmethanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea

Step 1: The solution of 1-fluoro-4-nitro-benzene (1.0 g, 7.1 mmol) andK₂CO₃ (2.0 g, 14.21 mmol) in DMSO (20 mL) was added phenylmethanethiol(0.88 g, 7.1 mmol) and the reaction was stirred at 100° C. overnight.After that, water (80 mL) was added to the mixture. The aqueous phasewas extracted with EA (80 mL×3). The organic layer was washed with brine(80 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column (PE/EA=100/1) to give the1-benzylsulfanyl-4-nitro-benzene (0.95 g, yield: 56%) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ=8.08 (d, J=8.8 Hz, 2H), 7.39-7.26 (m, 7H),4.25 (s, 2H).

Step 2: To the solution of 1-benzylsulfanyl-4-nitro-benzene (0.95 g, 3.9mmol) in DCM (15 mL) was added m-CPBA (2.3 g, 9.7 mmol) and the reactionwas stirred at room temperature overnight. The reaction was concentratedunder reduced pressure. The residue was purified by silica gel column(PE/EA=5/1) to give the 1-nitro-4-phenylmethanesulfonyl-benzene (790 mg,yield: 72%) as a white solid. MS: m/z 295.4 (M+18).

Step 3 to Step 5: Step 3 to Step 5 was similar to general procedure of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.28 (s, 1H), 8.51 (d, J=6.0 Hz, 2H),7.58-7.50 (m, 4H), 7.31-7.28 (m, 5H), 7.13-7.11 (m, 2H), 7.97 (t, J=6.0Hz, 1H), 4.56 (s, 2H), 4.34 (d, J=5.6 Hz, 2H), MS: m/z 381.9 (M+H⁺).

Example 302: Synthesis of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 4-methoxy-benzenethiol (420.6 mg, 3.0 mmol) inDMF (20 ml) was added 1-chloro-4-nitro-benzene (709 mg, 4.5 mmol) andK₂CO₃ (1.24 g, 9.1 mmol), the mixture was stirred at 80° C. overnight.The reaction was monitored by LCMS. Then the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column(PE/EA=100/1) to afford (4-methoxyphenyl)(4-nitrophenyl)sulfane (1.0 g,crude yield: >100%) as a yellow solid.

Step 2: To a solution of (4-methoxyphenyl)(4-nitrophenyl)sulfane (1.0 g,3.82 mmol) in DCM (50 ml) was added m-CPBA (1.97 g, 11.46 mmol), themixture was stirred at room temperature overnight. The reaction wasmonitored by TLC. Then the mixture was mixed with saturated aqueoussodium bicarbonate, the organic layer was concentrated in vacuum to givea residue, which was purified by a silica gel column (PE:EA=4:1) toafford 1-methoxy-4-((4-nitrophenyl)sulfonyl)benzene (1.09 g, 97.3%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.32 (d, J=8.0 Hz, 2H), 8.09(d, J=8.0 Hz, 2H), 7.89 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 3.86(s, 3H).

Step 3: To a solution of 1-methoxy-4-((4-nitrophenyl)sulfonyl)benzene(1.09 g, 3.71 mmol) in MeOH (50 mL), was added Pd/C (10% wet, 393 mg).The reaction mixture was stirred at room temperature under H₂ (1 atm)overnight. Pd/C was filtered off and the filtrate was concentrated todryness in vacuum. The residue was purified by flash to give4-(4-methoxy-benzenesulfonyl)-phenylamine (0.97 g, yield: 100%) as ayellow solid.

Step 4: To a solution of 4-(4-methoxy-benzenesulfonyl)-phenylamine (483mg, 1.83 mmol) in DCM (50 ml) was added phenyl chloroformate (573 mg,3.66 mmol) and TEA (364 mg, 3.66 mmol), the mixture was stirred at 0° C.for 1 hr. The reaction was monitored by TLC. The mixture wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=2/1) to afford[4-(4-methoxy-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (0.52g, 75%) as a white solid.

Step 5: To a solution of [4-(4-methoxy-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (300 mg, 0.78 mmol) in MeCN (25 mL) was addedpyridin-4-ylmethanamine (168.6 mg, 1.56 mmol) and TEA (157.8 mg, 1.56mmol), the mixture was stirred at 80° C. overnight. The reaction wasmonitored by LCMS, then the mixture was concentrated in vacuum to giveresidue, which was purified by prep-HPLC to give1-[4-(4-methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (74.6mg, yield: 24%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.26 (s,1H), 8.49 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz,2H), 7.59 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz,2H), 6.93 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 3.81 (s, 3H). MS:m/z 397.9 (M+H⁺).

Example 303: Synthesis of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(4-methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=8.98 (s, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.75 (d,J=8.0 Hz, 2H), 7.60-7.46 (m, 4H), 7.10 (d, J=8.0 Hz, 2H), 6.54 (t, J=8.0Hz, 2H), 4.14 (d, J=8.0 Hz, 2H), 3.81 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 304: Synthesis of Ethyl6-(3-(pyridin-4-ylmethyl)ureido)nicotinate

Step 1: To a solution of 6-amino-nicotinic acid ethylester (200 mg, 1.20mmol) in DCM (40 mL) was added phenyl chloroformate (227 mg, 1.45 mmol)and TEA (366 mg, 3.62 mmol). The mixture was stirred at room temperaturefor 1 hr. The reaction was monitored by TLC. Then the reaction mixturewas concentrated in vacuum to give a residue, which was purified byprep-TLC (PE/EA=10/1) to afford 6-phenoxycarbonylamino-nicotinic acidethylester (280 mg, yield: 81%) as a white solid.

Step 2: To a solution of 6-phenoxycarbonylamino-nicotinic acid ethylester (280 mg, 0.98 mmol) in dioxane (40 mL) was added4-(aminomethyl)pyridine (158 mg, 1.46 mmol) and TEA (297 mg, 2.92 mmol).The mixture was stirred at 80° C. overnight. The reaction was monitoredby TLC. Then the reaction mixture was concentrated in vacuum to give aresidue, which was purified by prep-TLC (DCM/MeOH=20/1) to afford6-3-pyridin-4-ylmethyl-ureido-nicotinic acid ethyl ester (215 mg,yield:73%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.88 (brs,1H), 8.76 (brs, 1H), 8.52-8.49 (m, 3H), 8.17 (dd, J=8.8, 2.4 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 7.30 (d, J=6.0 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H),4.25 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 301.1 (M+H⁺).

Example 305: Synthesis of1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3-chloro-benzenethiol (433.86 mg, 3.0 mmol) inDMF (20 mL) was added 1-chloro-4-nitro-benzene (709 mg, 4.5 mmol) andfollowed by K₂CO₃ (1.24 g, 9.0 mmol). The resulting mixture was stirredat 80° C. overnight. The reaction was monitored by TLC. Then the mixturewas diluted with H₂O (40 mL) and extracted with DCM (20 mL×2). Thecombined organic layers were concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=100:1) to afford4-(3-chlorophenylthio)-1-nitrobenzene (726 mg, yield: 91%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=8.11 (dd, J=6.8, 2.0 Hz, 2H), 7.51 (t,J=1.6 Hz, 1H), 7.44-7.36 (m, 3H), 7.25 (dd, J=6.8, 2.0 Hz, 2H).

Step 2: To a solution of 4-(3-chlorophenylthio)-1-nitrobenzene (726 mg,2.73 mmol) in DCM (40 mL) was added 3-chloro-benzenecarboperoxoic acid(2.02 g, 8.20 mmol, 30% H₂O contained). The resulting mixture wasstirred at room temperature overnight. The reaction was monitored byTLC. Then the mixture was mixed with saturated Na₂SO₃ (30 mL), andextracted with DCM (20 mL×2). The combined organic layers wereconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=10:1) to afford4-[(3-chlorophenyl)sulfonyl]-1-nitrobenzene (705 mg, yield: 88%) asyellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.36 (dd, J=9.2, 2.0 Hz, 2H),8.14 (dd, J=8.8, 2.0 Hz, 2H), 7.95 (t, J=1.6 Hz, 1H), 7.86 (dd, J=8.0,0.8 Hz, 1H), 7.62-7.58 (m, 1H), 7.50 (t, J=8.0 Hz, 1H).

Step 3: To a solution of 4-[(3-chlorophenyl)sulfonyl]-1-nitrobenzene(705 mg, 2.40 mmol) in EtOH/H₂O (v/v=40 mL/10 mL) was added powder iron(673 mg, 12.0 mmol), followed by NH₄Cl (643 mg, 12.0 mmol). Theresulting mixture was stirred at 80° C. overnight. The reaction wasmonitored by LC-MS. Then powder iron was filtered off, and the filtratewas concentrated in vacuum to give a residue, which was purified by areverse-phase column (5˜95% ACN in H₂O) to afford4-(3-chloro-benzenesulfonyl)-phenylamine (586 mg, yield: 92%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.84 (t, J=2.0 Hz, 1H), 7.81-7.77(m, 1H), 7.72-7.66 (m, 1H), 7.63-7.55 (m, 3H), 6.66-6.60 (m, 2H), 6.24(s, 2H).

Step 4: To a solution of 4-(3-chloro-benzenesulfonyl)-phenylamine (586mg, 2.19 mmol) in DCM (40 mL) was added phenyl carbonchloridate (514 mg,3.28 mmol), followed by TEA (664.5 mg, 6.57 mmol). The resulting mixturewas stirred at room temperature for 1 hour. The reaction was monitoredby TLC. Then the mixture was concentrated in vacuum to give a residue,which was purified by a silica gel column eluting with PE/EA=10/1 to 4/1to afford [4-(3-chloro-benzenesulfonyl)-phenyl]-carbamic acid phenylester (662 mg, yield: 78%) as a white solid.

Step 5: To a solution of [4-(3-Chloro-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (200 mg, 0.516 mmol) in ACN (40 mL) was addedc-pyridin-4-yl-methylamine (67 mg, 0.619 mmol), followed by TEA (156 mg,1.548 mmol). The resulting mixture was stirred at 80° C. for 2 hours.The reaction was monitored by LC-MS. Then the mixture was concentratedin vacuum to give a residue, which was purified by a prep-HPLC withNH₄OH as additive to afford1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (88.4mg, yield: 43%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.33 (s,1H), 8.50 (dd, J=4.8, 1.6 Hz, 2H), 7.93 (t, J=2.0 Hz, 1H), 7.89-7.83 (m,3H), 7.76-7.72 (m, 1H), 7.67-7.60 (m, 3H), 7.28 (d, J=5.6 Hz, 2H), 6.96(d, J=6.4 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 306: Synthesis of1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.32 (s, 1H), 8.49 (dd, J=4.4, 1.6 Hz, 2H),7.90 (dd, J=6.4, 2.0 Hz, 2H), 7.81 (dd, J=7.2, 1.6 Hz, 2H), 7.71-7.59(m, 4H), 7.27 (dd, J=4.4, 1.6 Hz, 2H), 6.95 (t, J=6.0 Hz, 1H), 4.33 (d,J=5.6 Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 307: Synthesis of1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.34 (s, 1H), 8.50 (dd, J=4.4, 1.2 Hz, 2H),8.23 (dd, J=8.0, 2.0 Hz, 1H), 7.78 (dd, J=7.2, 2.0 Hz, 2H), 7.73-7.59(m, 5H), 7.28 (d, J=2.0 Hz, 2H), 6.96 (t, J=5.6 Hz, 1H), 4.34 (d, J=6.4Hz, 2H). MS: m/z 401.9 (M+H⁺).

Example 308: Synthesis of1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.04 (s, 1H), 7.93 (t, J=2.0Hz, 1H), 7.90-7.82 (m, 3H), 7.77-7.71 (m, 1H), 7.67-7.59 (m, 3H),7.58-7.45 (m, 2H), 6.57 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.2 Hz, 2H). MS:m/z 390.9 (M+H⁺).

Example 309: Synthesis of1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.04 (s, 1H), 8.23 (dd,J=7.6, 1.6 Hz, 1H), 7.79-7.74 (m, 2H), 7.72-7.63 (m, 2H), 7.63-7.46 (m,5H), 6.56 (t, J=5.6 Hz, 1H), 4.16 (d, J=5.2 Hz, 2H). MS: m/z 390.9(M+H⁺).

Example 310: Synthesis of1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.61 (brs, 1H), 9.04 (s, 1H), 7.90 (dd,J=6.4, 2.0 Hz, 2H), 7.80 (dd, J=7.2, 2.0 Hz, 2H), 7.66 (dd, J=6.4, 2.0Hz, 2H), 7.60 (dd, J=7.2, 2.0 Hz, 2H), 7.57-7.48 (m, 2H), 6.57 (t, J=5.2Hz, 1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 390.9 (M+H⁺).

Example 311: Synthesis of1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.50 (dd, J=5.6, 1.6 Hz, 2H),7.96 (dd, J=8.0, 1.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.68-7.55 (m, 3H),7.28 (d, J=6.0 Hz, 2H), 7.20-7.11 (m, 2H), 6.93 (t, J=6.0 Hz, 1H), 4.34(d, J=6.0 Hz, 2H), 3.75 (s, 3H). MS: m/z 397.9 (M+H⁺).

Example 312: Synthesis of1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.30 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),7.82 (dd, J=6.8, 2.0 Hz, 2H), 7.62 (dd, J=7.2, 2.0 Hz, 2H), 7.51 (t,J=8.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.37 (t, J=2.0 Hz, 1H), 7.28 (dd,J=4.4, 1.6 Hz, 2H), 7.24-7.19 (m, 1H), 6.95 (t, J=6.0 Hz, 1H), 4.33 (d,J=5.6 Hz, 2H), 3.82 (s, 3H). MS: m/z 397.9 (M+H⁺).

Example 313: Synthesis of1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d6): δ=12.59 (brs, 1H), 8.94 (s, 1H), 7.95 (dd,J=8.0, 2.0 Hz, 1H), 7.96 (dd, J=6.8, 1.6 Hz, 2H), 7.66-7.60 (m, 1H),7.59-7.44 (m, 4H), 7.19-7.11 (m, 2H), 6.52 (t, J=5.6 Hz, 1H), 4.15 (d,J=5.2 Hz, 2H), 3.74 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 314: Synthesis of1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 8.99 (s, 1H), 7.81 (dd,J=7.2, 1.6 Hz, 2H), 7.64-7.48 (m, 5H), 7.47-7.42 (m, 1H), 7.39-7.35 (m,1H), 7.24-7.18 (m, 1H), 6.54 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H),3.82 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 315: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.16 (brs, 1H), 8.27 (s, 1H), 7.89 (d, J=8.0Hz, 2H), 81 (d, J=8.0 Hz, 2H), 7.70-7.55 (m, 5H), 7.00 (s, 1H), 6.83 (t,J=5.2 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 357.9 (M+H⁺).

Example 316: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(3-chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.60 (brs, 1H), 8.99 (s, 1H), 7.89 (dd,J=7.2, 1.6 Hz, 2H), 7.79 (dd, J=7.2, 1.6 Hz, 2H), 7.68-7.63 (m, 1H),7.62-7.46 (m, 6H), 6.54 (t, J=5.6 Hz, 1H), 4.14 (d, J=5.6 Hz, 2H). MS:m/z 356.9 (M+H⁺).

Example 317: Synthesis of1-(4-Benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 1-benzenesulfonyl-4-nitro-benzene (0.92 g, 3.5mmol) in MeOH/DCM (10 ml/10 ml) was added Pd/C (50% w/w, 0.31 g). Thereaction was stirred at room temperature under H₂ overnight. Then thereaction mixture was filtered. The filtrate was concentrated to give4-benzenesulfonyl-phenylamine (0.84 g, yield: quantitative) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ=7.88 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.4Hz, 2H), 7.51-7.43 (m, 3H), 6.65 (d, J=8.8 Hz, 2H), 4.14 (s, 2H).

Step 2: The solution of 4-benzenesulfonyl-phenylamine (300 mg, 1.3 mmol)and TEA (0.2 mL, 1.7 mmol) in DCM (20 mL) was degassed and purged withN₂. The mixture was stirred at 0° C. for a while. Then phenylchroloformate (250 mg, 1.6 mmol) was added and the mixture was stirredat room temperature for overnight. After that, the solution wasconcentrated under reduced pressure. The residue was purified by silicagel column (PE/EA=3/1) to give the (4-benzenesulfonyl-phenyl)-carbamicacid phenyl ester (340 mg, 74%) as a white solid.

Step 3: To a solution of (4-benzenesulfonyl-phenyl)-carbamic acid phenylester (200 mg, 0.57 mmol) in MeCN (5 mL) was added DMAP (83 mg, 0.68mmol) and 2-(aminomethyl)pyridine (62 mg, 0.57 mmol). The mixture wasrefluxed at 80° C. for overnight. After that, the solution wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give 1-(4-benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea(24.7 mg, yield: 11%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆):δ=9.30 (s, 1H), 8.49 (d, J=6.0 Hz, 2H), 7.89 (d, J=6.9 Hz, 2H), 7.81 (d,J=8.7 Hz, 2H), 7.66-7.57 (m, 5H), 7.27 (d, J=5.7 Hz, 2H), 6.93 (t, J=5.1Hz, 1H), 4.33 (d, J=6.4 Hz, 2H). MS: m/z 367.9 (M+H⁺).

Example 318: Synthesis of1-(4-Phenylmethanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea

Step 1: The solution of 1-fluoro-4-nitro-benzene (1.0 g, 7.1 mmol) andK₂CO₃ (2.0 g, 14.21 mmol) in DMSO (20 mL) was added phenylmethanethiol(0.88 g, 7.1 mmol) and the reaction was stirred at 100° C. overnight.After that, water (80 mL) was added to the mixture. The aqueous phasewas extracted with EA (80 mL×3). The organic layer was washed with brine(80 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Theresidue was purified by silica gel column (PE/EA=100/1) to give the1-benzylsulfanyl-4-nitro-benzene (0.95 g, yield: 56%) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ=8.08 (d, J=8.8 Hz, 2H), 7.39-7.26 (m, 7H),4.25 (s, 2H).

Step 2: To the solution of 1-benzylsulfanyl-4-nitro-benzene (0.95 g, 3.9mmol) in DCM (15 mL) was added m-CPBA (2.3 g, 9.7 mmol) and the reactionwas stirred at room temperature overnight. The reaction was concentratedunder reduced pressure. The residue was purified by silica gel column(PE/EA=5/1) to give the 1-nitro-4-phenylmethanesulfonyl-benzene (790 mg,yield: 72%) as a white solid. MS: m/z 295.4 (M+18).

Step 3 to Step 5: Step 3 to Step 5 was similar to general procedure of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.28 (s, 1H), 8.51 (d, J=6.0 Hz, 2H),7.58-7.50 (m, 4H), 7.31-7.28 (m, 5H), 7.13-7.11 (m, 2H), 7.97 (t, J=6.0Hz, 1H), 4.56 (s, 2H), 4.34 (d, J=5.6 Hz, 2H), MS: m/z 381.9 (M+H⁺).

Example 319: Synthesis of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 4-methoxy-benzenethiol (420.6 mg, 3.0 mmol) inDMF (20 ml) was added 1-chloro-4-nitro-benzene (709 mg, 4.5 mmol) andK₂CO₃ (1.24 g, 9.1 mmol), the mixture was stirred at 80° C. overnight.The reaction was monitored by LCMS. Then the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column(PE/EA=100/1) to afford (4-methoxyphenyl)(4-nitrophenyl)sulfane (1.0 g,crude yield: >100%) as a yellow solid.

Step 2: To a solution of (4-methoxyphenyl)(4-nitrophenyl)sulfane (1.0 g,3.82 mmol) in DCM (50 ml) was added m-CPBA (1.97 g, 11.46 mmol), themixture was stirred at room temperature overnight. The reaction wasmonitored by TLC. Then the mixture was mixed with saturated aqueoussodium bicarbonate, the organic layer was concentrated in vacuum to givea residue, which was purified by a silica gel column (PE:EA=4:1) toafford 1-methoxy-4-((4-nitrophenyl)sulfonyl)benzene (1.09 g, 97.3%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.32 (d, J=8.0 Hz, 2H), 8.09(d, J=8.0 Hz, 2H), 7.89 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 3.86(s, 3H).

Step 3: To a solution of 1-methoxy-4-((4-nitrophenyl)sulfonyl)benzene(1.09 g, 3.71 mmol) in MeOH (50 mL), was added Pd/C (10% wet, 393 mg).The reaction mixture was stirred at room temperature under H₂ (1 atm)overnight. Pd/C was filtered off and the filtrate was concentrated todryness in vacuum. The residue was purified by flash to give4-(4-methoxy-benzenesulfonyl)-phenylamine (0.97 g, yield: 100%) as ayellow solid.

Step 4: To a solution of 4-(4-methoxy-benzenesulfonyl)-phenylamine (483mg, 1.83 mmol) in DCM (50 ml) was added phenyl chloroformate (573 mg,3.66 mmol) and TEA (364 mg, 3.66 mmol), the mixture was stirred at 0° C.for 1 hr. The reaction was monitored by TLC. The mixture wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=2/1) to afford[4-(4-methoxy-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (0.52g, 75%) as a white solid.

Step 5: To a solution of [4-(4-methoxy-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (300 mg, 0.78 mmol) in MeCN (25 mL) was addedpyridin-4-ylmethanamine (168.6 mg, 1.56 mmol) and TEA (157.8 mg, 1.56mmol), the mixture was stirred at 80° C. overnight. The reaction wasmonitored by LCMS, then the mixture was concentrated in vacuum to giveresidue, which was purified by prep-HPLC to give1-[4-(4-methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (74.6mg, yield: 24%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.26 (s,1H), 8.49 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz,2H), 7.59 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.10 (d, J=8.0 Hz,2H), 6.93 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 3.81 (s, 3H). MS:m/z 397.9 (M+H⁺).

Example 320: Synthesis of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared as described in example1-[4-(4-methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=8.98 (s, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.75 (d,J=8.0 Hz, 2H), 7.60-7.46 (m, 4H), 7.10 (d, J=8.0 Hz, 2H), 6.54 (t, J=8.0Hz, 2H), 4.14 (d, J=8.0 Hz, 2H), 3.81 (s, 3H). MS: m/z 386.9 (M+H⁺).

Example 321: Synthesis of 4-(3-Benzyl-3-methyl-ureido)-benzoic acidethyl ester

A solution of 4-phenoxycarbonylamino-benzoic acid ethyl ester (50 mg,0.175 mmol), methyl-pyridin-4-ylmethyl-amine (23.5 mg, 0.193 mmol) andEt₃N (53.15 mg, 0.526 mmol) in 1,4-dioxane (2 ml) was stirred at 90° C.overnight. The mixture was concentrated and purified by prep-HPLC togive 4-(3-benzyl-3-methyl-ureido)-benzoic acid ethyl ester (14 mg.yield: 25.5%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.81 (brs,2H), 8.01 (brs, 2H), 7.92 (d, J=6.8 Hz, 2H), 7.58 (d, J=6.8 Hz, 2H),4.91 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.23 (s, 3H), 1.37 (t, J=7.2 Hz,3H). MS: m/z 314.0 (M+H⁺).

Example 322: Synthesis of1-[(Pyridin-4-ylmethyl)-carbamoyl]-1H-indazole-5-carboxylic acid ethylester

Step 1: A solution of 1H-indazole-5-carboxylic acid ethyl ester (175 mg,0.92 mmol), phenyl chloroformate (217 mg, 1.39 mmol) and Et₃N (0.3 mL)in THF (2 ml) was stirred at 80° C. for 6 hrs. The mixture wasconcentrated to give crude indazole-1,5-dicarboxylic acid 5-ethyl ester1-phenyl ester, which was used for next step directly without furtherpurification. MS: m/z 311.6 (M+H)⁺.

Step 2: A solution of indazole-1,5-dicarboxylic acid 5-ethyl ester1-phenyl ester (280 mg, crude), pyridin-4-ylmethanamine (97.5 mg, 0.903mmol) and Et3N (273 mg, 2.7 mmol) in [1,4]dioxane (3 mL) was stirred at100° C. for 2 hrs under MW irradiation. The mixture was concentrated andthe brown oil was purified by prep-HPLC to give1-[(pyridin-4-ylmethyl)-carbamoyl]-1H-indazole-5-carboxylic acid ethylester (96.5 mg, yield: 33%) as a white solid. ¹H NMR (400 MHz, DMSO-d6):δ=9.27 (t, J=6.2 Hz, 1H), 8.61 (t, J=2.0 Hz, 1H), 8.58-8.55 (m, 1H),8.52 (dd, J=4.4, 1.6 Hz, 2H), 8.34 (d, J=8.8 Hz, 1H), 8.13 (dd, J=8.8,1.6 Hz, 1H), 7.37 (d, J=6.0 Hz, 2H), 4.53 (d, J=6.4 Hz, 2H), 4.36 (d,J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H). MS: m/z 325.0 (M+H⁺).

Example 323: Synthesis of4-(2-Oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid ethylester and 4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid

Step 1: To a solution of 4-amino-benzoic acid ethyl ester (446 mg, 2.7mmol) in THF (5 mL), was added 1-chloro-2-isocyanato-ethane (0.27 mL,2.9 mmol). The mixture was stirred at 40° C. overnight. After that,water (20 mL) and EA (20 mL) was added. The mixture was extracted withEA ((20 mL×2). The extracts were dried over Na₂SO₄ and concentrated togive 4-[3-(2-chloro-ethyl)-ureido]-benzoic acid ethyl ester (673 mg,yield: 92%) as a yellow solid.

Step 2: To a solution of 4-[3-(2-chloro-ethyl)-ureido]-benzoic acidethyl ester (269 mg, 1.00 mmol) in DMF (5 mL), was added NaH (197 mg,4.9 mmol). The suspension was stirred for half an hour at roomtemperature under N₂, followed by the addition of4-chloromethyl-pyridine (183 mg, 1.12 mmol). The mixture was stirredovernight at room temperature. After that, NH₄Cl (40 mL) and EA (20 mL)was added. The aqueous phase was extracted with EA (20 mL×2). Theextracts were washed with brine (20 mL×2), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography (EA) and recrystallized from MeCN to give4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid ethylester (100 mg, yield: 31%) as a yellow solid. The aqueous phase waspurified by reverse phase column chromatography (MeCN/H₂O=5˜95%) toafford 4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid (20mg, yield: 7%) as a white solid.

4-(2-Oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid ethylester: ¹H NMR (400 MHz, DMSO-d₆): δ=8.54 (d, J=6.0 Hz, 2H), 7.93 (d,J=9.2 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.33 (d, J=6.0 Hz, 2H), 4.46 (s,2H), 4.28 (q, J=7.2 Hz, 2H), 3.92 (t, J=8.0 Hz, 2H), 3.46 (t, J=8.0 Hz,2H), 1.31 (t, J=7.2 Hz, 3H). MS: m/z 325.9 (M+H⁺).

4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acid: ¹H NMR(400 MHz, DMSO-d₆): δ=8.55 (d, J=5.2 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H),7.72 (d, J=8.8 Hz, 2H), 7.33 (d, J=5.2 Hz, 2H), 4.46 (s, 2H), 3.92 (t,J=8.0 Hz, 2H), 3.46 (t, J=8.0 Hz, 2H). MS: m/z 297.9 (M+H⁺).

Example 324: Synthesis ofN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

Step 1: To a solution of 4-nitro-phenylamine (2.0 g, 14.5 mmol) andpyridine (3 mL, 39.1 mmol) in DCM (100 mL) was added phenylchloroformate (2.5 mL, 20.3 mmol) dropwise at 0° C. After stirring atroom temperature for 2 hrs, the reaction mixture was diluted with DCM(50 mL), washed with water (50 mL). The DCM solution was dried overNa₂SO₄ and concentrated. The residue was washed with (PE/EA=8/1) to give(4-nitro-phenyl)-carbamic acid phenyl ester (2.4 g, yield: 64%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ=8.19 (d, J=8.8 Hz, 2H), 7.59 (d,J=8.8 Hz, 2H), 7.47-7.39 (m, 3H), 7.28 (t, J=8.0 Hz, 1H), 7.19 (d, J=7.6Hz, 2H).

Step 2: To a solution of (4-nitro-phenyl)-carbamic acid phenyl ester(200 mg, 0.8 mmol) and TEA (0.2 mL, 1.5 mmol) in MeCN (5 mL) was addedPyridin-4-ylmethanamine (90 mg, 0.8 mmol). After stirring at 80° C. for16 hrs, the precipitation was collected and washed with MeCN (2 mL) togive 1-(4-nitro-phenyl)-3-pyridin-4-ylmethyl-urea (200 mg, yield: 95%)as a white solid.

Step 3: A mixture of 1-(4-nitro-phenyl)-3-pyridin-4-ylmethyl-urea (200mg, 0.7 mmol) and 10% Pd/C (50% w/w, 70 mg) in MeOH (25 mL) was stirredat room temperature for 16 hrs under H₂ atmosphere (balloon). Thereaction mixture was filtered to remove catalyst. The filtrate wasconcentrated to give 1-(4-amino-phenyl)-3-pyridin-4-ylmethyl-urea (160mg, crude) as a pale yellow solid.

Step 4: To a stirring solution of1-(4-amino-phenyl)-3-pyridin-4-ylmethyl-urea (160 mg, 0.7 mmol) and TEA(0.3 mL, 2.0 mmol) in DMF (4 mL) was added benzenesulfonyl chloride (180mg, 1.0 mmol). After stirring at room temperature for 1 h, the reactionmixture was diluted with H₂O (20 mL) and extracted with EA (20 mL×4).The combined EA was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column(DCM/MeOH=30/1) and then washed with MeOH (5 mL) to giveN-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide (50 mg,yield: 18%, two steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.91 (s, 1H), 8.61 (s, 1H), 8.48 (dd, J=4.4, 1.2 Hz, 2H), 7.69 (d,J=7.6 Hz, 2H), 7.61-7.50 (m, 3H), 7.26-7.23 (m, 4H), 6.92 (d, J=8.8 Hz,2H), 6.67 (t, J=5.6 Hz, 1H), 4.29 (d, J=5.6 Hz, 2H). MS: m/z 382.9(M+H⁺).

Example 325: Synthesis of2-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.59 (s, 1H), 8.54 (s, 1H), 8.47 (d, J=5.6 Hz,2H), 7.66 (d, J=6.4 Hz, 1H), 7.53 (t, J=8.2 Hz, 1H), 7.24-7.16 (m, 5H),7.00-6.92 (m, 3H), 6.64 (t, J=6.0 Hz, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.91(s, 3H). MS: m/z 412.9 (M+H⁺).

Example 326: Synthesis of3-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.89 (s, 1H), 8.61 (s, 1H), 8.48 (dd, J=1.6, 4.8Hz, 2H), 7.43 (t, J=8.0 Hz, 1H), 7.26-7.23 (m, 5H), 7.20-7.13 (m, 2H),6.93 (d, J=9.2 Hz, 2H), 6.67 (t, J=6.0 Hz, 1H), 4.29 (d, J=6.0 Hz, 2H),3.91 (s, 3H). MS: m/z 412.9 (M+H⁺).

Example 327: Synthesis of4-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.76 (s, 1H), 8.59 (s, 1H), 8.48 (d, J=6.0 Hz,2H), 7.61 (d, J=9.2 Hz, 2H), 7.26-7.23 (m, 4H), 7.03 (d, J=8.8 Hz, 2H),6.91 (d, J=8.8 Hz, 2H), 6.67 (t, J=6.0 Hz, 1H), 4.28 (t, J=6.8 Hz, 2H),3.78 (s, 3H). MS: m/z 412.9 (M+H⁺).

Example 328: Synthesis of2-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=10.23 (s, 1H), 8.60 (s, 1H), 8.47-8.48 (m, 2H),7.93 (d, J=6.8 Hz, 1H), 7.62-7.60 (m, 2H), 7.48-7.47 (m, 1H), 7.23-7.25(s, 4H), 6.96 (d, J=7.6 Hz, 2H), 6.67 (s, 1H), 4.28 (d, J=4.0 Hz, 2H).MS: m/z 416.9 (M+H⁺).

Example 329: Synthesis of3-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=10.03 (s, 1H), 8.67 (s, 1H), 8.51 (d, J=6.4 Hz,2H), 7.69-7.68 (m, 2H), 7.62-7.54 (m, 2H), 7.30-7.27 (m, 4H), 6.92 (d,J=8.4 Hz, 2H), 6.70 (t, J=6.4 Hz, 1H), 4.31 (d, J=5.6 Hz, 2H). MS: m/z416.9 (M+H⁺).

Example 330: Synthesis of4-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

To a solution of 1-(4-amino-phenyl)-3-pyridin-4-ylmethyl-urea (200 mg,0.8 mmoL) and Et₃N (0.3 mL, 2.0 mmoL) in DMF (11 mL) was added4-chloro-benzenesulfonyl chloride (210 mg, 1.0 mmoL) at 0° C. Themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with EA (35 mL) and washed with H₂O (40 mL), brine (40 mL),dried over Na₂SO₄ and concentrated to dryness in vacuum. The residue waswashed with MeOH (4 mL) and CH₃CN (4 mL) to give4-chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide(60 mg, yield: 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.98(s, 1H), 8.64 (s, 1H), 8.48 (d, J=6.0 Hz, 2H), 7.68-7.60 (m, 4H),7.28-7.25 (m, 4H), 6.92 (d, J=8.4 Hz, 2H), 6.68 (t, J=6.0 Hz, 1H), 4.30(d, J=6.0 Hz, 2H). MS: m/z 416.9 (M+H⁺).

Example 331: Synthesis ofN-[4-(3-Benzyl-ureido)-phenyl]-C-phenyl-methanesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(300 MHz, DMSO-d6): δ=9.56 (s, 1H), 8.70 (s, 1H), 8.50 (dd, J=1.2, 4.4Hz, 2H), 7.38-7.35 (m, 5H), 7.29-7.25 (m, 4H), 7.09 (d, J=8.8 Hz, 2H),6.71 (t, J=6.0 Hz, 1H), 4.35-4.32 (m, 4H), MS: m/z 397.0 (M+H⁺).

Example 332: Synthesis of1-(2-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.73 (s, 1H), 8.66 (s, 1H), 8.50 (d, J=5.6 Hz,2H), 7.48 (d, J=6.8 Hz, 1H), 7.42-7.35 (m, 5H), 7.28 (d, J=5.6 Hz, 2H),7.10 (d, J=8.8 Hz, 2H), 6.70 (t, J=6.0 Hz, 1H), 4.52 (s, 2H), 4.32 (d,J=6.0 Hz, 2H). MS: m/z 430.9 (M+H⁺).

Example 333: Synthesis of1-(3-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.60 (s, 1H), 8.69 (s, 1H), 8.50 (d, J=6.0 Hz,2H), 7.43-7.36 (m, 4H), 7.33 (s, 1H), 7.28 (d, J=5.6 Hz, 2H), 7.22 (d,J=6.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.71 (t, J=6.0 Hz, 1H), 4.42 (s,2H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 430.9 (M+H⁺).

Example 334: Synthesis of1-(4-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=9.55 (s, 1H), 8.68 (s, 1H), 8.50 (d, J=6.4 Hz,2H), 7.43 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.29-7.27 (m, 4H),7.07 (d, J=9.2 Hz, 2H), 6.7 (t, J=6 Hz, 1H), 4.38 (s, 2H), 4.32 (d, J=6Hz, 2H). MS: m/z 430.9 (M+H⁺).

Example 335: Synthesis ofN-Methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

Step 1: To a solution of 4-nitro-phenylamine (5.0 g, 36.2 mmoL), TEA (10mL, 69.3 mmoL) and DMAP (2.2 g, 18.0 mmoL) in DCM (100 mL) was addedBOC₂O (9.5 g, 43.5 mmoL) at room temperature. After stirring at roomtemperature for 16 hrs, the precipitation was removed by filtration andthe filtrate was washed with aq.HCl (1 N, 50 mL), Sat.NaHCO₃ (20 mL),dried and concentrated. The residue was purified by silica gel column(PE/EA=20/1) to give (4-nitro-phenyl)-carbamic acid tert-butyl ester(4.4 g, yield: 51%) as a yellow solid. ¹H NM (400 MHz, CDCl₃): δ=8.17(d, J=9.6 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.08 (brs, 1H), 1.54 (s, 9H).

Step 2: A suspension of (4-nitro-phenyl)-carbamic acid tert-butyl ester(400 mg, 1.7 mmoL) and 10% Pd/C (50% w/w, 80 mg) in MeOH (6 mL) wasstirred at room temperature for 16 hrs under H₂ atmosphere (balloon).The reaction mixture was filtered to remove catalyst and the filtratewas concentrated to give (4-amino-phenyl)-carbamic acid tert-butyl ester(300 mg, yield: 86%) as a red solid. MS: m/z 153.3 (M-55).

Step 3: To a solution of (4-amino-phenyl)-carbamic acid tert-butyl ester(200 mg, 1.0 mmoL) and Et₃N (0.3 mL, 2.0 mmoL) in DCM (6 mL) was addedphenyl-methanesulfonyl chloride (200 mg, 1.1 mmoL) at 0°. After stirringat room temperature for 2 hrs, the reaction mixture was concentrated andthe residue was purified by silica gel column (PE/EA=7/1) to give(4-phenylmethanesulfonylamino-phenyl)-carbamic acid tert-butyl ester(190 mg, yield: 54%) as a red solid.

Step 4: To a stirring solution of(4-phenylmethanesulfonylamino-phenyl)-carbamic acid tert-butyl ester(300 mg, 0.8 mmol) and K₂CO₃ (230 mg, 1.7 mmol) in DMF (6 mL) was addedCH₃I (140 mg, 1.0 mmol). After stirring at room temperature for 16 hrs,the reaction mixture was diluted with H₂O (30 mL) and extracted with EA(30 mL×3). The combined EA was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was washed with (PE/EA=2/1) to give[4-(methyl-phenylmethanesulfonyl-amino)-phenyl]-carbamic acid tert-butylester (240 mg, yield: 77%) as a white solid. ¹H NMR (400 MHz, CDCl₃):δ=7.40-7.32 (m, 7H), 7.17 (d, J=9.2 Hz, 2H), 6.51 (s, 1H), 4.25 (s, 2H),3.10 (s, 3H), 1.52 (s, 9H).

Step 5: To a solution of[4-(methyl-phenylmethanesulfonyl-amino)-phenyl]-carbamic acid tert-butylester (240 mg, 0.7 mmol) in DCM (5 mL) was added HCl/MeOH (4 M, 5 mL).After stirring at room temperature for 2 hrs, the reaction mixture wasconcentrated to giveN-(4-amino-phenyl)-N-methyl-C-phenyl-methanesulfonamide (crude) as awhite solid.

Step 6: To a solution ofN-(4-amino-phenyl)-N-methyl-C-phenyl-methanesulfonamide (crude) and TEA(0.3 mL, 1.9 mmol) in DCM (10 mL) was added phenyl chloroformate (0.1mL, 0.8 mmol) dropwise at 0° C. After stirring at this temperature for20 min, the reaction mixture was diluted with DCM (30 mL), washed withaq.HCl (1 N, 20 mL) and Sat.NaHCO₃ (20 mL). The DCM solution was driedover Na₂SO₄ and concentrated to give[4-(methyl-phenylmethanesulfonyl-amino)-phenyl]-carbamic acid phenylester (crude) as a white solid.

Step 7: A mixture of[4-(methyl-phenylmethanesulfonyl-amino)-phenyl]-carbamic acid phenylester (crude), Pyridin-4-ylmethanamine (70 mg, 0.6 mmol) and TEA (0.2mL, 1.3 mmol) in MeCN (10 mL) was stirred at 80° C. for 1 h and thenconcentrated. The residue was diluted by DCM (50 mL) and extracted byaq.HCl (1 N, 30 mL). The acidic layer was basified by Sat.NaHCO₃ to pH=8and then extracted with DCM (30 mL×4). The combined DCM was dried overNa₂SO₄ and concentrated. The residue was washed with MeCN (10 mL) togiveN-methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(90 mg, yield: 34%, three steps) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ=8.81 (s, 1H), 8.50 (d, J=5.6 Hz, 2H), 7.41-7.35 (m, 7H),7.29 (d, J=5.6 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 6.76 (t, J=6.0 Hz, 1H),4.45 (s, 2H), 4.33 (d, J=6.0 Hz, 2H), 3.15 (s, 3H). MS: m/z 410.9(M+H⁺).

Example 336: Synthesis ofN-Isopropyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

Step 1: This step was similar to general procedure ofN-methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.

Step 2: To a stirring solution of(4-benzenesulfonylamino-phenyl)-carbamic acid tert-butyl ester (600 mg,1.7 mmol) and K₂CO₃ (480 mg, 3.4 mmol) in DMF (10 mL) was added2-iodo-propane (440 mg, 2.6 mmol). After stirring at 90° C. for 24 hrs,the reaction mixture was diluted with H₂O (30 mL) and extracted with EA(30 mL×3). The combined EA was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column (PE/EA=10/1)to give [4-(benzenesulfonyl-isopropyl-amino)-phenyl]-carbamic acidtert-butyl ester (530 mg, yield: 79%) as a white solid. ¹H NMR (300 MHz,CDCl₃): δ=7.76-7.73 (m, 2H), 7.59-7.53 (m, 1H), 7.50-7.43 (m, 2H), 7.34(d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.54 (s, 1H), 4.67-4.57 (m,1H), 1.53 (s, 9H), 1.04 (d, J=6.3 Hz, 6H).

Step 3-5: These three steps were similar to general procedure ofN-methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ=8.87 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),7.74-7.65 (m, 3H), 7.59 (td, J=6.4, 1.6 Hz, 2H), 7.42-7.38 (m, 2H), 7.28(dd, J=4.4, 1.6 Hz, 2H), 6.87-6.84 (m, 2H), 6.79 (t, J=6.0 Hz, 1H),4.46-4.41 (m, 1H), 4.33 (d, J=6.0 Hz, 2H), 0.94 (d, J=7.2 Hz, 6H). MS:m/z 424.9 (M+H⁺).

Example 337: Synthesis ofN-Methyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide

The title compound was prepared as described in exampleN-methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (300 MHz, DMSO-d6): δ=8.81 (s, 1H), 8.50 (d, J=5.7 Hz, 2H), 7.67(t, J=5.4 Hz, 1H), 7.60-7.57 (m, 2H), 7.51-7.48 (m, 2H), 7.34 (d, J=9.0Hz, 2H), 7.27 (d, J=5.1 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 6.76 (t, J=5.4Hz, 1H), 4.31 (d, J=5.7 Hz, 2H), 3.07 (s, 3H). MS: m/z 397.0 (M+H⁺).

Example 338: Synthesis ofN-Isopropyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

The title compound was prepared as described in exampleN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d6): δ=8.86 (s, 1H), 8.50 (dd, J=2.0, 4.4 Hz, 2H),7.46-7.36 (m, 7H), 7.28 (d, J=6.0 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.78(t, J=6.0 Hz, 1H), 4.46 (s, 2H), 4.33 (d, J=6.0 Hz, 2H), 4.16-4.12 (m,1H), 0.96 (d, J=6.8 Hz, 6H). MS: m/z 439.0 (M+H⁺).

Example 339: Synthesis ofN-[4-(3-Oxazol-5-ylmethyl-ureido)-phenyl]-benzenesulfonamide

Step 1: To a solution of (4-nitro-phenyl)-carbamic acid phenyl ester(800 mg, 3.1 mmol) and TEA (1.4 mL, 9.3 mmol) in MeCN (20 mL) was addedoxazol-5-ylmethanamine hydrochloride (420 mg, 3.1 mmol). After stirringat 80° C. for 1 hr, the reaction mixture was concentrated and purifiedby silica gel column (DCM/MeOH=20/1) to give1-(4-nitro-phenyl)-3-oxazol-5-ylmethyl-urea (810 mg, yield: >100%) as ayellow solid.

Step 2-3: These two steps were similar to general procedure ofN-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide. ¹H NMR(400 MHz, DMSO-d₆): δ=9.91 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H),7.70-7.67 (m, 2H), 7.61-7.50 (m, 3H), 7.22 (d, J=9.2 Hz, 2H), 6.97 (s,1H), 6.91 (d, J=9.2 Hz, 2H), 6.55 (t, J=5.6 Hz, 1H), 4.32 (d, J=5.6 Hz,2H). MS: m/z 372.9 (M+H⁺).

Example 340: Synthesis ofN-Oxazol-5-ylmethyl-2-(4-phenylmethanesulfonylamino-cyclohexa-1,5-dienyl)-acetamide

The title compound was prepared as described in exampleN-[4-(3-oxazol-5-ylmethyl-ureido)-phenyl]-C-phenyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d6): δ=9.54 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H),7.36-7.34 (m, 5H), 7.27-7.26 (m, 2H), 7.08 (d, J=9.2 Hz, 2H), 7.00 (s,1H), 6.57 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz, 4H). MS: m/z 386.9(M+H⁺).

Example 341: Synthesis ofN-{4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-phenyl}-benzenesulfonamide

Step 1: To a solution of (4-benzenesulfonylamino-phenyl)-carbamic acidtert-butyl ester (1.0 g, 2.9 mmol) in DCM (10 mL) was added HCl/MeOH (4M, 10 mL). After stirring at room temperature for 16 hrs, the reactionmixture was concentrated to dryness. The residue was diluted withSat.NaHCO₃ (30 mL) and the aqueous phase was extracted with EA (40mL×2). The combined organic layer was washed with brine (30 mL), driedover Na₂SO₄ and concentrated to giveN-(4-amino-phenyl)-benzenesulfonamide (700 mg, yield: 98%) as a whitesolid.

Step 2: To a solution of N-(4-amino-phenyl)-benzenesulfonamide (200 mg,0.8 mmol) and pyridine (200 mg, 2.4 mmol) in DCM (10 mL) was addedphenyl chloroformate (160 mg, 1.0 mmol) dropwise at 0° C. After stirringat this temperature for 20 min, the reaction mixture was diluted withDCM (40 mL), washed with aq.HCl (1 N, 30 mL) and Sat.NaHCO₃ (20 mL). TheDCM solution was dried over Na₂SO₄, concentrated and washed with(PE/EA=4/1) to give (4-benzenesulfonylamino-phenyl)-carbamic acid phenylester (280 mg, yield: 94%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆):δ=10.11 (s, 1H), 10.06 (s, 1H), 7.71 (d, J=6.9 Hz, 2H), 7.60-7.50 (m,3H), 7.44-7.32 (m, 4H), 7.27-7.16 (m, 3H), 7.02 (d, J=9.0 Hz, 2H).

Step 3: A mixture of (4-benzenesulfonylamino-phenyl)-carbamic acidphenyl ester (130 mg, 0.4 mmol), (1H-pyrazol-4-yl)methanamine (120 mg,crude) and TEA (0.2 mL, 1.4 mmol) in MeCN (15 mL) was stirred at 80° C.for 16 hrs and then concentrated. The residue was purified by silicaflash column (0% to 10% MeOH in DCM) to giveN-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-benzenesulfonamide (80mg, yield: 61%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=12.59(brs, 1H), 9.88 (s, 1H), 8.32 (s, 1H), 7.69-7.66 (m, 2H), 7.61-7.50 (m,5H), 7.22 (dd, J=7.2, 2.0 Hz, 2H), 6.91 (dd, J=7.2, 2.0 Hz, 2H), 6.25(t, J=5.6 Hz, 1H), 4.10 (d, J=5.6 Hz, 2H). MS: m/z 371.9 (M+H⁺).

Example 342: Synthesis ofN-(4-(3-((1H-pyrazol-4-yl)methyl)ureido)phenyl)-1-phenylmethanesulfonamide

The title compound was prepared as described in exampleN-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-benzenesulfonamide. HNMR (300 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 9.51 (s, 1H), 8.38 (s, 1H),7.53-7.51 (m, 2H), 7.37-7.24 (m, 7H), 7.10-7.06 (m, 2H), 6.28 (t, J=5.4Hz, 1H), 4.34 (s, 2H), 4.14 (d, J=5.4 Hz, 2H). MS: m/z 385.9 (M+H⁺).

Example 343: Synthesis ofN-(4-{3-[1-(4-Methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-ureido}-phenyl)-benzenesulfonamide

Step 1: A mixture of 1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g,35.7 mmol), PMBCl (6.2 g, 39.3 mmol) and K₂CO₃ (7.4 g, 53.6 mmol) inMeCN (100 mL) was refluxed for 16 hrs. Excessive K₂CO₃ was removed byfiltration and the filtrate was concentrated to dryness. The residue waspurified by silica gel column (PE/EA=5/1) to give1-(4-methoxy-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (9.5 g,yield: >100%) as a colorless oil.

Step 2: To a solution of 1-(4-methoxy-benzyl)-1H-pyrazole-4-carboxylicacid ethyl ester (1.0 g, 3.8 mmol) in THF (10 mL) was added LAH (300 mg,7.7 mmol) portion wise at 0° C. After stirring at room temperature for 2hrs, H₂O (0.3 mL), 15% NaOH (0.3 mL) and H₂O (0.9 mL) were then addeddropwise at 0° C. The mixture was stirred at room temperature foranother 20 min, dried over MgSO₄ and filtered. The filtrate wasconcentrated to give [1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-methanol(860 mg, yield: >100%) as a white solid.

Step 3: To a solution of [1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-methanol(860 mg, crude) and Et₃N (1.1 mL, 7.6 mmol) in DCM (20 mL) was addedMsCl (500 mg, 4.3 mmol) dropwise at 0° C. After stirring at roomtemperature for 20 min, the reaction mixture was diluted with DCM (30mL) and washed with water (30 mL). The DCM solution was dried overNa₂SO₄ and concentrated. The residue was dissolved in DMF (10 mL) andpotassium phthalimide (870 mg, 4.7 mmol) was added. After stirring at80° C. for 2 hrs, the reaction mixture was poured to water (50 mL) andextracted with EA (50 mL×3). The combined organic layer was washed withbrine (40 mL×3), dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column (PE/EA=2/1) to give2-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-isoindole-1,3-dione (880mg, yield: 64%) as a white solid.

Step 4: To a solution of2-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-isoindole-1,3-dione (880mg, 2.5 mmol) in EtOH (45 mL) was added hydrazine hydrate (98%, 260 mg,5.1 mmol). After stirring at 80° C. for 2 hrs, the precipitation wasremoved by filtration and the filtrate was concentrated to dryness. Theresidue was purified by silica gel column (DCM/MeOH/NH₃.H₂O=10/1/0.03)to give C-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-methylamine (250 mg,yield: 45%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ=7.47 (s, 1H),7.28 (s, 1H), 7.20 (d, J=8.7 Hz, 2H), 6.88 (dd, J=6.6, 2.1 Hz, 2H), 5.21(s, 2H), 3.80 (s, 3H), 3.75 (s, 2H).

Step 5: To a solution ofC-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-methylamine (288 mg, 1.3 mmoL)and Et₃N (0.4 ml, 2.8 mmoL) in MeCN (10 mL) was added(4-nitro-phenyl)-carbamic acid phenyl ester (350 mg, 1.3 mmoL) at 0° C.Then the mixture was stirred at 80° C. for 30 min.

The reaction mixture was purified with recrystallization to give1-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-3-(4-nitro-phenyl)-urea(380 mg, yield: 74%) as a white solid.

Step 6: A suspension of1-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-3-(4-nitro-phenyl)-urea(380 mg, 1 mmoL) and Pd/C (98 mg) in MeOH/DCM (9 mL/9 mL) under H₂atmosphere (balloon) was stirred at room temperature for 2 hrs. Thereaction mixture was filtered to remove catalyst and the filtrate wasconcentrated to give1-(4-amino-phenyl)-3-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-urea(crude).

Step 7: To a solution of1-(4-amino-phenyl)-3-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-urea(350 mg, 1 mmoL) and Et₃N (0.3 mL, 2.1 mmoL) in DMF (4 mL) was addedbenzenesulfonyl chloride (211 mg, 1.2 mmoL) at 0° C. Then the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasdiluted with H₂O (50 mL) and extracted with EA. The organic layers weredried over Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by silica flash column (4% MeOH in DCM) to giveN-(4-{3-[1-(4-methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-ureido}-phenyl)-benzenesulfonamide(320 mg, yield: 65%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=7.70(d, J=7.6 Hz, 2H), 7.56-7.53 (m, 2H), 7.48-7.44 (m, 3H), 7.20-7.16 (m,4H), 6.95 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.19 (s, 2H), 4.2(s, 2H), 3.76 (s, 3H). MS: m/z 491.9 (M+H⁺).

Example 344: Synthesis ofN-Phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

Step 1: To a solution of (4-nitro-phenyl)-methanesulfonyl chloride (300mg, 1.3 mmol) in DCM (5 mL) was added aniline (145 mg, 1.56 mmol) andTEA (263.1 mg, 2.6 mmol), Then the mixture was stirred at rt for 1 hr.The reaction was monitored by TLC, The mixture was concentrated invacuum to give residue, which was purified by a silica gel column(PE/EA=3:1) to give c-(4-nitro-phenyl)-n-phenyl-methanesulfonamide (151mg, yield: 80%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.92 (s,1H), 8.21 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.32 (t, J=8.0 Hz,2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 4.68 (s, 2H).

Step 2: To a solution of c-(4-nitro-phenyl)-n-phenyl-methanesulfonamide(150 mg, 0.51 mmol) in MeOH (10 mL), was added Pd/C (10% wet, 54.06 mg).The reaction mixture was stirred at room temperature under H₂ (1 atm)for 1 hr. Pd/C was filtered off and the filtrate was concentrated todryness in vacuum. The residue was purified by a silica gel column(PE/EA=3/1) to give c-(4-amino-phenyl)-N-phenyl-methanesulfonamide (130mg, yield: 100%) as a yellow solid.

Step 3: To a solution of c-(4-Amino-phenyl)-n-phenyl-methanesulfonamide(130 mg, 0.49 mmol) in DCM 10 mL), was added phenyl chlorformate (153.4mg. 0.98 mmol) and TEA (99.17 mg, 0.58 mmol). The mixture was stirred atroom temperature overnight. Then the reaction was monitored by TLC. Themixture was concentrated in vacuum to give residue, which was purifiedby a silica gel column (PE/EA=3/1) to afford(4-phenylsulfamoylmethyl-phenyl)-carbamic acid phenyl ester (151 mg.80%) as a yellow solid.

Step 4: To a solution of (4-phenylsulfamoylmethyl-phenyl)-carbamic acidphenyl ester (151 mg, 0.39 mmol) in dioxane 10 mL), was addedpyridin-4-ylmethanamine (84.3 mg, 0.78 mmol) and DIEA (100.62 mg. 0.78mmol). The mixture was stirred at 90° C. overnight. The reaction wasmonitored by LCMS. Then the mixture was concentrated in vacuum to giveresidue. The residue was purified by prep-HPLC to given-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(30 mg, yield: 15.8%) as a white solid. ¹H NMR (400 MHz, DMSO-d6):δ=9.74 (s, 1H), 8.76 (s, 1H), 8.50 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz,2H), 7.32 (t, J=8.0 Hz, 2H). 7.28 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz,2H) 7.13-7.05 (m, 3H), 6.75 (t, J=8.0 Hz, 1H), 4.37-4.30 (m, 4H). MS:m/z 383.0 (M+H⁺). MS: m/z 397.9 (M+H⁺).

Example 345: Synthesis ofN-Methyl-N-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

The title compound was prepared as described in examplen-methyl-n-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d6): δ=8.77 (s, 1H), 8.50 (d, J=8.0 Hz, 2H),7.43-7.33 (m, 4H), 7.32-7.20 (m, 7H), 6.76 (t, J=8.0 Hz, 1H), 4.40 (s,2H), 4.33 (d, J=8.0 Hz, 2H), 3.18 (s, 3H). MS: m/z 410.9 (M+H⁺).

Example 346: Synthesis of Ethyl4-(3-((1,2,3,4-tetrahydroquinolin-4-yl)methyl)ureido)benzoate

The title compound was prepared as described in example 4-(3 ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=8.97 (brs, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 6.96(d, J=7.6 Hz, 1H), 6.87 (t, J=8.0 Hz, 1H), 6.50-6.39 (m, 3H), 5.72 (s,1H), 4.26 (q, J=7.2 Hz, 2H), 3.32-3.09 (m, 4H), 2.88-2.79 (m, 1H),1.84-1.65 (m, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 354.0 (M+H⁺).

Example 347: Synthesis of Ethyl4-(3-(quinolin-4-ylmethyl)ureido)benzoate

The title compound was prepared as described in example ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.21 (brs, 1H), 8.87 (d, J=4.4 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.06(d, J=8.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.79 (t, J=7.2 Hz, 1H), 7.67(t, J=7.2 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.45 (d, J=4.0 Hz, 1H), 6.99(d, J=6.0 Hz, 1H), 4.85 (d, J=5.6 Hz, 2H), 4.26 (q, J=6.8 Hz, 2H), 1.30(t, J=7.2 Hz, 3H). MS: m/z 350.0 (M+H⁺).

Example 348: Synthesis of Ethyl 4-(3-(isoquinolin-5-yl)ureido)benzoate

To a solution of 4-isocyanato-benzoic acid ethyl ester (100 mg, 0.523mmol) in dioxane (20 mL) was added isoquinolin-5-ylamine (90.5 mg, 0.628mmol), followed by TEA (158 mg, 1.57 mmol). The resulting mixture wasstirred at 90° C. overnight. The reaction was monitored by LC-MS. Thenthe mixture was concentrated in vacuum to give a residue, which waspurified by prep-TLC (DCM/MeOH=20/1) to afford ethyl4-(3-(isoquinolin-5-yl)ureido)benzoate (167.2 mg, yield: 95%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.49 (brs, 1H), 9.34 (s, 1H), 9.03(s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.98 (d, J=5.6Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.71-7.62 (m,3H), 4.29 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). MS: m/z 336.0(M+H⁺).

Example 349: Synthesis of Ethyl4-(3-(1H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate

Step 1: To a solution of 1H-pyrrolo[2,3-c]pyridine (1 g, 8.47 mmol) inH₂SO₄ (5 mL) was added 69% HNO₃ (533 mg, 8.47 mmol) at 0° C. Afterstirred at 0° C. for 2 hrs, the reaction mixture was allowed to warm toroom temperature and stirred overnight. The mixture was then poured intoH₂O (100 mL) and basified by NaOH powder to pH>7. Then the mixture wasextracted by EA (100 mL×3), dried over anhydrous Na₂SO₄, and evaporatedin vacuum to afford 3-nitro-1H-pyrrolo[2,3-c]pyridine (690 mg, 50%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.94 (s, 1H), 8.85 (s, 1H),8.44 (d, J=5.2 Hz, 1H), 8.02 (dd, J=5.6, 1.2 Hz, 1H). MS: m/z 164.0(M+H)⁺.

Step 2: To a solution of 3-nitro-1H-pyrrolo[2,3-c]pyridine (200 mg, 1.23mmol) in MeOH (20 mL) was added 10% Pd/C (130 mg, 0.12 mmol). Afterstirred at balloon hydrogen atmosphere for 2 hrs, the mixture wasfiltered. The filtrate was evaporated in vacuum to give1H-pyrrolo[2,3-c]pyridin-3-amineas a crude product which was used fornext step without further purification.

Step 3: To a solution of 1H-pyrrolo[2,3-c]pyridin-3-amine (crude, 1.23mmol) in THF (20 mL) was added 4-isocyanato-benzoic acid ethyl ester(235 mg, 1.23 mmol) and the mixture was heated to 60° C. for 3 hrs. Thenthe mixture was evaporated in vacuum to remove THF. The residue waspartitioned in a mixture of H₂O (50 mL) and EA (50 mL). The aqueousphase was then extracted by EA (50 mL×2). Organic phase was combined,dried over anhydrous Na₂SO₄, and evaporated in vacuum. The residue waspurified by pre-HPLC to afford ethyl4-(3-(1H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate (120 mg, 30.1%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=11.36 (s, 1H), 9.10 (s, 1H),8.75-8.72 (m, 2H), 8.11 (d, J=5.2 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H), 7.76(d, J=2.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.51 (d, J=5.2 Hz, 1H), 4.28(q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H). MS: m/z 324.9 (M+H)⁺.

Example 350: Synthesis of Ethyl4-(3-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate

Step 1: To a solution of 3-nitro-1H-pyrrolo[2,3-c]pyri dine (250 mg,1.53 mmol in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 61mg, 1.53 mmol). After stirred at 0° C. for 10 min, dimethylsulfate (193mg, 1.53 mmol) was added dropwise. After stirred at 0° C. for 3 hrs, themixture was partitioned in a mixture of ethyl acetate (50 mL) and H₂O(50 mL) and the aqueous phase was extracted by ethyl acetate (50 mL×2).Organic phase was combined, dried over anhydrous Na₂SO₄, and evaporatedin vacuum. The residue was purified by flash column (ACN in water: 5% to50%) to afford 1-methyl-3-nitro-1H-pyrrolo[2,3-c]pyridine (30 mg, 11%)as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.94 (d, J=0.8 Hz, 1H),8.61 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.12 (dd, J=5.2, 0.8 Hz, 1H), 4.06(s, 3H). MS: m/z 178.0 (M+H)⁺.

Step 2: To a solution of 1-methyl-3-nitro-1H-pyrrolo[2,3-c]pyridine (25mg, 0.14 mmol) in MeOH (10 mL) was added 10% Pd/C (15 mg, 0.014 mmol).After stirred at balloon hydrogen atmosphere for 2 hrs, the mixture wasfiltered. The filtrate was evaporated in vacuum to give1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylamine as a crude product which wasused for next step without further purification.

Step 3: To a solution of 1-methyl-1H-pyrrolo[2,3-c]pyridin-3-ylamine(crude, 0.14 mmol) in THF (10 mL) was added 4-isocyanato-benzoic acidethyl ester (26.8 mg, 0.14 mmol) and the mixture was stirred at roomtemperature overnight. Then the mixture was evaporated in vacuum. Theresidue was purified by pre-TLC (DCM/MeOH=10/1) to afford ethyl4-(3-(1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate (8 mg, 17%)as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=9.02 (s, 1H), 8.16 (d,J=6.0 Hz, 1H), 8.12 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.90 (d, J=6.0 Hz,1H), 7.60 (d, J=8.4 Hz, 2H), 4.35 (q, J=7.2 Hz, 2H), 4.04 (s, 3H), 1.38(t, J=7.2 Hz, 3H). MS: m/z 339.0 (M+H)⁺.

Example 351: Synthesis of Ethyl4-(3-(6-methyl-6H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate

Step 1: To a solution of 3-nitro-1H-pyrrolo[2,3-c]pyridine (250 mg, 1.53mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 61 mg,1.53 mmol). After stirred at 0° C. for 10 min, the mixture was addeddimethylsulfate (193 mg, 1.53 mmol) dropwise. After stirred at 0° C. for3 hrs, the mixture was partitioned in a mixture of H₂O (50 mL) and EA(50 mL). The aqueous phase was then extracted by EA (50 mL×2). Organicphase was combined, dried over anhydrous Na₂SO₄, and evaporated invacuum. The residue was washed with MeOH (5 mL) to afford6-methyl-3-nitro-6H-pyrrolo[2,3-c]pyridine (70 mg, 26%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.09 (s, 1H), 8.65 (s, 1H), 8.25(dd, J=6.8, 1.2 Hz, 1H), 8.14 (d, J=6.8 Hz, 1H), 4.26 (s, 3H). MS: m/z178.0 (M+H)⁺.

Step 2: To a solution of 6-methyl-3-nitro-6H-pyrrolo[2,3-c]pyridine (70mg, 0.4 mmol) in MeOH (15 mL) was added 10% Pd/C (42 mg, 0.04 mmol).After stirred at balloon hydrogen atmosphere for 3 hrs, the mixture wasfiltered. The filtrate was evaporated in vacuum to give6-methyl-6H-pyrrolo[2,3-c]pyridin-3-ylamine as a crude product which wasused for next step without further purification.

Step 3: To a solution of 6-methyl-6H-pyrrolo[2,3-c]pyridin-3-ylamine(crude, 0.4 mmol) in THF (15 mL) was added 4-isocyanato-benzoic acidethyl ester (76.5 mg, 0.4 mmol) and the mixture was stirred at 60° C.for 3 hrs. Then the mixture was evaporated in vacuum to remove THF. Theresidue was partitioned in a mixture of H₂O (30 mL) and EA (50 mL). Theaqueous phase was then extracted by EA (50 mL×2). Organic phase wascombined, dried over anhydrous Na₂SO₄, and evaporated in vacuum. Theresidue was purified by pre-HPLC to afford ethyl4-(3-(6-methyl-6H-pyrrolo[2,3-c]pyridin-3-yl)ureido)benzoate (10 mg,7.4%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=9.08 (s, 1H), 8.38(s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.8Hz, 2H), 7.62 (d, J=9.2 Hz, 2H), 4.40-4.32 (m, 5H), 1.38 (t, J=7.2 Hz,3H). MS: m/z 339.0 (M+H)⁺.

Example 352: Synthesis of Ethyl4-(furo[3,2-c]pyridine-2-carboxamido)benzoate

Step 1: To a solution of 4-chloro-furo[3,2-c]pyridine (700 mg, 39.65mmoL), Pd/C (158 mg) and TEA (1 mL, 6.97 mmoL) in MeOH (16 mL) under H₂atmosphere (balloon) at room temperature. Then the mixture was stirredat room temperature for 2 hrs. The reaction mixture was filtered toremove catalyst and the filtrate was concentrated to dryness in vacuumand the residue was purified by silica gel column (PE/EA=6/1) to givefuro[3,2-c]pyridine (320 mg, yield: 59%) as a white oil. ¹H NMR (400MHz, DMSO-d₆): δ=9.00 (s, 1H), 8.48 (d, J=6 Hz, 1H), 8.12 (d, J=2.4 Hz,1H), 7.70 (d, J=6 Hz, 1H), 7.13 (dd, J=2.0, 0.8 Hz, 1H).

Step 2: To a solution of furo[3,2-c]pyridine (300 mg, 2.5 mmoL) in THFwas added n-BuLi (1.5 mL, 3.75 mmoL) dropwisely at −70° C. and stirredat −70° C. for 1 hr. Then dry CO₂ is passed through the reaction mixtureand the temperature is allowed to rise gradually in 2 hrs. The mixturewas diluted with H₂O/LiOH (15 mL/100 mg) and extracted by EA (30 mL×1).Then the H₂O layer is acidified to pH 5 with HCl. Then the mixture wasfiltered to give furo[3,2-c]pyridine-2-carboxylic acid (172 mg, yield:42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=13.83 (brs, 1H),9.10 (s, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.81-7.79 (m, 2H).

Step 3: To a solution of furo[3,2-c]pyridine-2-carboxylic acid (60 mg,0.37 mmoL), 4-amino-benzoic acid ethyl ester (73 mg, 0.44 mmoL) andDIPEA (0.3 mL, 1.7 mmoL) in DMF (4 mL) was added HATU (210 mg, 0.55mmoL) at room temperature. Then the mixture was stirred at roomtemperature for 3 hrs.

The reaction mixture was poured into H₂O (30 mL) and extracted with EA(20 mL×4). The combined EA extracts was washed with H₂O (60 mL), brine(60 mL), dried over Na₂SO₄ and concentrated to dryness in vacuum. Theresidue was purified by silica gel column (PE/EA=3/5) to give ethyl4-(furo[3,2-c]pyridine-2-carboxamido)benzoate (50 mg, yield: 44%) as awhite solid. ¹H NMR (300 MHz, CDCl₃): δ=9.10 (s, 1H), 8.68 (d, J=5.7 Hz,1H), 8.47 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.72(s, 1H), 7.55 (d, J=6.0 Hz, 1H), 4.39 (q, J=6.9 Hz, 2H), 1.42 (t, J=6.9Hz, 3H). MS: m/z 311.1 (M+H⁺).

Example 353: Synthesis of Furo[3,2-c]pyridine-2-carboxylic acid[4-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-amide

The title compound was prepared using general procedure of4-[(furo[3,2-c]pyridine-2-carbonyl)-amino]-benzoic acid ethyl ester. ¹HNMR (400 MHz, DMSO-d₆): δ=11.03 (s, 1H), 9.17 (s, 1H), 8.64 (d, J=6.0Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.97 (s, 1H), 7.87-7.82 (m, 3H),7.16-7.13 (m, 4H), 4.20 (s, 2H), 3.32 (overlap, 2H), 2.87 (t, J=5.2 Hz,2H). MS: m/z 433.9 (M+H⁺).

Example 354: Synthesis of Ethyl6-(3-(pyridin-4-ylmethyl)ureido)nicotinate

Step 1: To a solution of 6-amino-nicotinic acid ethylester (200 mg, 1.20mmol) in DCM (40 mL) was added phenyl chloroformate (227 mg, 1.45 mmol)and TEA (366 mg, 3.62 mmol). The mixture was stirred at room temperaturefor 1 hr. The reaction was monitored by TLC. Then the reaction mixturewas concentrated in vacuum to give a residue, which was purified byprep-TLC (PE/EA=10/1) to afford 6-phenoxycarbonylamino-nicotinic acidethylester (280 mg, yield: 81%) as a white solid.

Step 2: To a solution of 6-phenoxycarbonylamino-nicotinic acid ethylester (280 mg, 0.98 mmol) in dioxane (40 mL) was added4-(aminomethyl)pyridine (158 mg, 1.46 mmol) and TEA (297 mg, 2.92 mmol).The mixture was stirred at 80° C. overnight. The reaction was monitoredby TLC. Then the reaction mixture was concentrated in vacuum to give aresidue, which was purified by prep-TLC (DCM/MeOH=20/1) to afford6-3-pyridin-4-ylmethyi-ureido-nicotinic acid ethyl ester (215 mg,yield:73%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.88 (brs,1H), 8.76 (brs, 1H), 8.52-8.49 (m, 3H), 8.17 (dd, J=8.8, 2.4 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 7.30 (d, J=6.0 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H),4.25 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 301.1 (M+H⁺).

Example 355: Synthesis of Ethyl5-(3-(pyridin-4-ylmethyl)ureido)picolinate

Step 1: To a solution of 5-amino-pyridine-2-carboxylic acid ethyl ester(220 mg, 1.33 PGP mmol) in DCM (40 mL) was added phenyl chloroformate(251 mg, 1.60 mmol) and TEA (395 mg, 3.90 mol). The mixture was stirredat room temperature for 1 hr. The reaction was monitored by TLC. Thenthe reaction mixture was concentrated in vacuum to give a residue, whichwas purified by prep-TLC (PE/EA=10/1) to afford5-phenoxycarbonylamino-pyridine-2-carboxylic acid ethyl ester (150 mg,yield: 40%) as a white solid.

Step 2: To a solution of 5-phenoxycarbonylamino-pyridine-2-carboxylicacid ethyl ester (150 mg, 0.52 mmol) in dioxane (40 mL) was added4-(aminomethyl) pyridine (85 mg, 0.79 mmol) and TEA (159 mg, 1.57 mmol).The mixture was stirred at 80° C. overnight. The reaction was monitoredby TLC. Then the reaction mixture was concentrated in vacuum to give aresidue, which was purified by prep-TLC (DCM/MeOH=20/1) to afford ethyl5-(3-(pyridin-4-ylmethyl)ureido)picolinate (53 mg, yield: 34%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.46 (brs, 1H), 8.64 (d, J=2.4Hz, 1H), 8.52 (d, J=5.6 Hz, 2H), 8.09 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.31 (d, J=5.6 Hz, 2H), 7.09 (brs, 1H), 4.36 (d, J=5.6Hz, 2H), 4.28 (q, J=7.2 Hz, 2H). 1.31 (t, J=7.2 Hz, 3H). MS:m/z 301.1(M+H⁺).

Example 356: Synthesis of 6-(3-Pyridin-4-ylmethyl-ureido)-nicotinamide

Step 1: To a solution of 6-amino-nicotinic acid ethyl ester (200 mg,1.20 mmol) in DCM (20 mL) was added phenyl chloroformate (226 mg, 1.44mmol), followed by TEA (365 mg, 3.60 mmol). The resulting mixture wasstirred at room temperature for 1 hr. The reaction was monitored by TLC.Then the mixture was concentrated in vacuum to give a residue, which waspurified by a silica gel column eluting with DCM to afford6-phenoxycarbonylamino-nicotinic acid ethyl ester (322 mg, yield: 94%)as a white solid.

Step 2: To a solution of 6-phenoxycarbonylamino-nicotinic acid ethylester (322 mg, 1.12 mmol) in dioxane (40 mL) was addedpyridin-4-ylmethanamine (146 mg, 1.35 mmol), followed by TEA (342 mg,3.36 mmol). The resulting mixture was stirred at 90° C. overnight. Thereaction was monitored by LC-MS. Then the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column(DCM/MeOH=50/1 as eluent) to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid ethyl ester (324 mg,yield: 96%) as a white solid.

Step 3: To a solution of 6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acidethyl ester (324 g, 1.08 mmol) in THF/H₂O (20 mL+5 mL) was added LiOH(136 mg, 3.24 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction was monitored by TLC. Then THF wasremoved in vacuum to give an aqueous residue, which was acidified topH=45 with conc. HCl. The solid precipitated from the mixture wasfiltered. The cake was washed with H₂O (20 mL×2) and air dried to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid (480 g, crude) as ayellow solid.

Step 4: To a solution of 6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid(100 mg, 0.367 mmol) in DMF (10 mL) was added HATU (418 mg, 1.10 mmol)and DIEA (142 mg, 1.10 mmol). The mixture was stirred at roomtemperature for 30 mins. Then NH₄Cl (84 mg, 1.84 mmol) was added intothe reaction mixture. The resulting reaction mixture was stirred at roomtemperature overnight. The reaction was monitored by LC-MS. Then themixture was concentrated in vacuum to give a residue, which was purifiedby prep-HPLC with NH₄OH as additive to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinamide (53.2 mg, yield: 53%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.70 (brs, 1H), 69 (d, J=1.2Hz, 1H), 8.63-8.54 (m, 1H), 8.51 (d, J=4.8 Hz, 2H), 8.12 (dd, J=8.8, 2.0Hz, 1H), 7.95 (brs, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.39 (brs, 1H), 7.30(d, J=5.2 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H). MS: m/z 272.0 (M+H⁺).

Example 357: Synthesis of 5-(3-(pyridin-4-ylmethyl)ureido)picolinamide

The title compound was prepared as described in example6-(3-pyridin-4-ylmethyl-ureido)-nicotinamide. ¹H NMR (400 MHz, CD₃OD):δ=8.63 (s, 1H), 8.46 (d, J=6.0 Hz, 2H), 7.98-8.03 (m, 2H), 7.41 (d,J=6.0 Hz, 2H), 4.48 (s, 2H). MS: m/z 272.0 (M+H⁺).

Example 358: Synthesis of Ethyl5-(3-(pyridin-4-ylmethyl)ureido)picolinate

Step 1: To a solution of 5-amino-pyridine-2-carboxylic acid ethyl ester(220 mg, 1.33 mmol) in DCM (40 mL) was added phenyl chloroformate (251mg, 1.60 mmol) and TEA (395 mg, 3.90 mol). The mixture was stirred atroom temperature for 1 hr. The reaction was monitored by TLC. Then thereaction mixture was concentrated in vacuum to give a residue, which waspurified by prep-TLC (PE/EA=10/1) to afford5-phenoxycarbonylamino-pyridine-2-carboxylic acid ethyl ester (150 mg,yield: 40%) as a white solid.

Step 2: To a solution of 5-phenoxycarbonylamino-pyridine-2-carboxylicacid ethyl ester (150 mg, 0.52 mmol) in dioxane (40 mL) was added4-(aminomethyl) pyridine (85 mg, 0.79 mmol) and TEA (159 mg, 1.57 mmol).The mixture was stirred at 80° C. overnight. The reaction was monitoredby TLC. Then the reaction mixture was concentrated in vacuum to give aresidue, which was purified by prep-TLC (DCM/MeOH=20/1) to afford ethyl5-(3-(pyridin-4-ylmethyl)ureido)picolinate (53 mg, yield: 34%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.46 (brs, 1H), 8.64 (d, J=2.4Hz, 1H), 8.52 (d, J=5.6 Hz, 2H), 8.09 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d,J=8.4 Hz, 1H), 7.31 (d, J=5.6 Hz, 2H), 7.09 (brs, 1H), 4.36 (d, J=5.6Hz, 2H), 4.28 (q, J=7.2 Hz, 2H). 1.31 (t, J=7.2 Hz, 3H). MS:m/z 301.1(M+H⁺).

Example 359: Synthesis of 6-(3-Pyridin-4-ylmethyl-ureido)-nicotinamide

Step 1: To a solution of 6-amino-nicotinic acid ethyl ester (200 mg,1.20 mmol) in DCM (20 mL) was added phenyl chloroformate (226 mg, 1.44mmol), followed by TEA (365 mg, 3.60 mmol). The resulting mixture wasstirred at room temperature for 1 hr. The reaction was monitored by TLC.Then the mixture was concentrated in vacuum to give a residue, which waspurified by a silica gel column eluting with DCM to afford6-phenoxycarbonylamino-nicotinic acid ethyl ester (322 mg, yield: 94%)as a white solid.

Step 2: To a solution of 6-phenoxycarbonylamino-nicotinic acid ethylester (322 mg, 1.12 mmol) in dioxane (40 mL) was addedpyridin-4-ylmethanamine (146 mg, 1.35 mmol), followed by TEA (342 mg,3.36 mmol). The resulting mixture was stirred at 90° C. overnight. Thereaction was monitored by LC-MS. Then the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column(DCM/MeOH=50/1 as eluent) to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid ethyl ester (324 mg,yield: 96%) as a white solid.

Step 3: To a solution of 6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acidethyl ester (324 g, 1.08 mmol) in THF/H₂O (20 mL+5 mL) was added LiOH(136 mg, 3.24 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction was monitored by TLC. Then THF wasremoved in vacuum to give an aqueous residue, which was acidified topH=45 with conc. HCl. The solid precipitated from the mixture wasfiltered. The cake was washed with H₂O (20 mL×2) and air dried to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid (480 g, crude) as ayellow solid.

Step 4: To a solution of 6-(3-pyridin-4-ylmethyl-ureido)-nicotinic acid(100 mg, 0.367 mmol) in DMF (10 mL) was added HATU (418 mg, 1.10 mmol)and DIEA (142 mg, 1.10 mmol). The mixture was stirred at roomtemperature for 30 mins. Then NH₄Cl (84 mg, 1.84 mmol) was added intothe reaction mixture. The resulting reaction mixture was stirred at roomtemperature overnight. The reaction was monitored by LC-MS. Then themixture was concentrated in vacuum to give a residue, which was purifiedby prep-HPLC with NH₄OH as additive to afford6-(3-pyridin-4-ylmethyl-ureido)-nicotinamide (53.2 mg, yield: 53%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.70 (brs, 1H), 69 (d, J=1.2Hz, 1H), 8.63-8.54 (m, 1H), 8.51 (d, J=4.8 Hz, 2H), 8.12 (dd, J=8.8, 2.0Hz, 1H), 7.95 (brs, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.39 (brs, 1H), 7.30(d, J=5.2 Hz, 2H), 4.45 (d, J=6.0 Hz, 2H). MS: m/z 272.0 (M+H⁺).

Example 360: Synthesis of 5-(3-(pyridin-4-ylmethyl)ureido)picolinamide

The title compound was prepared as described in example6-(3-pyridin-4-ylmethyl-ureido)-nicotinamide. ¹H NMR (400 MHz, CD₃OD):δ=8.63 (s, 1H), 8.46 (d, J=6.0 Hz, 2H), 7.98-8.03 (m, 2H), 7.41 (d,J=6.0 Hz, 2H), 4.48 (s, 2H). MS: m/z 272.0 (M+H⁺).

Example 361: Synthesis of 4-[2-(Pyridin-4-ylamino)-acetylamino]-benzoicacid ethyl ester

Step1: To a suspension of 4-amino-benzoic acid ethyl ester (200 mg, 1.2mmol) and K₂CO₃ (501 mg, 3.6 mmol) in DCM (4 mL) at 0° C. was added2-chloroacetyl chloride (164 mg, 1.45 mmol). The mixture was stirred at40° C. overnight. The reactant was diluted with water (10 mL) andextracted with DCM (10 mL×3). The combined organic layers wereconcentrated and purified by prep-TLC to give4-(2-chloro-acetylamino)-benzoic acid ethyl ester (200 mg, yield: 68.5%)as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=10.66 (s, 1H), 7.94 (d,J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 4.40-4.14 (m, 4H), 1.31 (t, J=7.2Hz, 3H).

Step 2: A solution of 4-(2-chloro-acetylamino)-benzoic acid ethyl ester(120 mg, 0.497 mmol), pyridin-4-ylamine (51.4 mg, 0.547 mmol) and DIEA(128.4 mg, 0.995 mmol) in DMF (4 mL) was stirred at 100° C. overnight.The mixture was evaporated and the residue was diluted with water. Theresulting solid was filtered and purified by prep-TLC to give4-[2-(pyridin-4-ylamino)-acetylamino]-benzoic acid ethyl ester (44 mg,yield: 29.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=11.23 (s,1H), 8.32 (s, 2H), 8.15 (d, J=7.3 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.77(d, J=8.8 Hz, 2H), 6.87 (d, J=7.2 Hz, 2H), 5.20 (s, 2H), 4.29 (q, J=7.1Hz, 2H), 1.31 (t, J=7.2 Hz, 3H). MS: m/z 300.1 (M+H⁺).

Example 362: Synthesis of4-[(Pyridin-4-ylcarbamoylmethyl)-amino]-benzoic acid ethyl ester

Step 1: To a solution of pyridin-4-ylamine (200 mg, 2.12 mmol) and DIEA(823 mg 0.6.38 mmol) in THF (3 mL) was added 2-chloroacetyl chloride(288 mg. 2.55 mmol), then the mixture was stirred at 30° C. for 2 hrs.The mixture was concentrated and the residue was purified by prep-TLC(DCM/MeOH=10/1) to give 4-amino-benzoic acid ethyl ester (200 mg, yield:55.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=11.06 (s, 1H),8.46 (dd, J=4.8, 1.4 Hz, 2H), 7.62 (dd, J=4.8, 1.4 Hz, 2H), 4.36 (s,2H).

Step 2: A solution of 2-chloro-N-(pyridin-4-yl)acetamide (100 mg, 0.588mmol), 4-amino-benzoic acid ethyl ester (106.7 mmol, 0.65 mmol) and DIEA(152 mg, 1.176 mmol) in DMF was stirred at 90° C. overnight. The mixturewas filtered and the filtrate was purified by prep-HPLC to give4-[(pyridin-4-ylcarbamoylmethyl)-amino]-benzoic acid ethyl ester (4 mg,2.3%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=8.05 (d, J=6.9 Hz,2H), 7.98 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 6.87 (d, J=6.8 Hz,2H), 5.12 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H). MS:m/z 300.0 (M+H⁺).

Example 363: Synthesis of 4-[3-Pyridin-4-yl-ureido)-methyl]-benzoic acidethyl ester

Step 1: A solution of pyridin-4-yl-carbamic acid phenyl ester (190 mg,0.88 mmol), 4-bromo-benzylamine (182 mg, 0.968 mmol) and Et₃N (269 mg,2.64 mmol) in 1,4-dioxane (2 mL) was stirred at 90° C. overnight. Themixture was concentrated and the residue was purified by prep-TLC togive 1-(4-bromo-benzyl)-3-pyridin-4-yl-urea (230 mg. yield: 84.6%) as awhite solid. MS: m/z 308.1 (M+H)⁺.

Step 2: To a solution of 1-(4-bromo-benzyl)-3-pyridin-4-yl-urea (270 mg,0.88 mmol) and Et₃N (178 mg, 1.76 mmol) in EtOH (5 mL), Pd(dppf)Cl₂ (60mg, 0.088 mmol) was added, the mixture was stirred at 80° C. under COballoon pressure for 3 days. The reaction was filtered, and the filtratewas concentrated to dryness. The residue was purified by prep-HPLC togive 4-[(3-pyridin-4-yl-ureido)-methyl]-benzoic acid ethyl ester (18.1mg, yield: 6.68%). MS: m/z 300.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6):δ=9.16 (s, 1H), 8.29 (d, J=5.4 Hz, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.43 (d,J=8.0 Hz, 2H), 7.38 (d, J=5.3 Hz, 2H), 6.99 (dd, J=8.4, 3.2 Hz, 1H),4.39 (d, J=6.0 Hz, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).MS: m/z 300.0 (M+H⁺).

Example 364: Synthesis of4-[(2-Pyridin-4-yl-cyclopropanecarbonyl)-amino]-benzoic acid ethyl ester

Step 1: A mixture of 3-pyridin-4-yl-acrylic acid (1.2 g, 8.1 mmol), EDCI(2.1 g, 10.5 mmol), HOBt (1.6 g, 10.5 mmol) and DIPEA (4.2 mL, 24.0mmol) in DMF (30 mL) was stirred for 1 hr at room temperature, thenO,N-dimethyl-hydroxylamine.HCl (950 mg, 9.7 mmol) was added. Afterstirring at room temperature for 16 hrs, the reaction mixture wasdiluted with H₂O (100 mL) and extracted with EA (40 mL×6). The combinedEA was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by silica flash column (50% to 100% EA in PE) togive N-methoxy-N-methyl-3-pyridin-4-yl-acrylamide (1.2 g, yield: 78%) asa yellow oil. ¹H NMR (400 MHz, CDCl₃): δ=8.64 (d, J=6.0 Hz, 2H), 7.65(d, J=15.6 Hz, 1H), 7.41 (d, J=6.0 Hz, 2H), 7.20 (d, J=15.6 Hz, 1H),3.78 (s, 3H), 3.33 (s, 3H).

Step 2: To a suspension of trimethylsulfoxonium iodide (1.7 g, 7.6 mmol)in DMSO (10 mL) was added NaH (60%, 300 mg, 7.6 mmol) portionwise. Afterstirring at room temperature for 1 hr, a solution ofN-methoxy-N-methyl-3-pyridin-4-yl-acrylamide (1.2 g, 6.3 mmol) in DMSO(5 mL) was added dropwise. The reaction mixture was stirred at roomtemperature for another 16 hrs. The reactant was diluted with H₂O (50mL) and extracted with EA (30 mL×5). The combined EA was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bysilica flash column (30% to 100% EA in PE) to give2-pyridin-4-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (570 mg,yield: 44%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ=8.48 (dd, J=4.4,1.6 Hz, 2H), 7.02 (dd, J=4.4, 1.6 Hz, 2H), 3.70 (s, 3H), 3.24 (s, 3H),2.50-2.43 (m, 2H), 1.75-1.68 (m, 1H), 1.38-1.32 (m, 1H).

Step 3: To a solution of 2-pyridin-4-yl-cyclopropanecarboxylic acidmethoxy-methyl-amide (150 mg, 0.7 mmol) in Et₂O (4 mL) was added H₂O(0.03 mL, 1.5 mmol) and t-BuOK (490 mg, 4.4 mmol). After stirring atroom temperature for 16 hrs, the reaction mixture was diluted with H₂O(5 mL) and acidified by aq.HCl (1 N) to pH=3. The solution was purifiedby reverse phase column (0% to 5% MeCN in H₂O) to give2-pyridin-4-yl-cyclopropanecarboxylic acid (90 mg, yield: 62%) as awhite solid. ¹H NMR (400 MHz, D₂O): δ=8.48 (d, J=6.4 Hz, 2H), 7.64 (d,J=6.4 Hz, 2H), 2.60-2.50 (m, 1H), 2.07-2.00 (m, 1H), 1.75-1.66 (m, 1H),1.52-1.47 (m, 1H).

Step 4: To a stirring solution of 2-pyridin-4-yl-cyclopropanecarboxylicacid (60 mg, 0.3 mmol), 4-amino-benzoic acid ethyl ester (60 mg, 0.4mmol) and DIPEA (0.2 mL, 0.9 mmol) in DMF (2 mL) was added HATU (170 mg,0.5 mmol). After stirring at room temperature for 2 hrs, the reactionmixture was diluted with H₂O (10 mL) and extracted with EA (10 mL×3).The combined EA was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel column (PE/EA=1/2)to give 4-[(2-pyridin-4-yl-cyclopropanecarbonyl)-amino]-benzoic acidethyl ester (24 mg, yield: 25%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ=10.75 (s, 1H), 8.55 (dd, J=4.8, 1.2 Hz, 2H), 7.91 (d, J=8.8Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.42 (dd, J=4.8, 1.2 Hz, 2H), 4.28 (q,J=7.2 Hz, 2H), 2.56-2.50 (m, 1H), 2.36-2.31 (m, 1H), 1.69-1.56 (m, 2H),1.31 (t, J=7.2 Hz, 3H). MS: m/z 311.0 (M+H⁺).

Example 365: Synthesis of Ethyl4-((2,3-dioxo-4-((pyridin-4-ylmethyl)amino)cyclobutyl)amino)benzoate

Step 1: A mixture of 3,4-diethoxycyclobutane-1,2-dione (183 mg, 1.1mmol) and ethyl 4-aminobenzoate (177 mg, 1.1 mmol) in EtOH (5.0 mL) wasstirred at 30° C. for 48 hrs. The mixture was concentrated in vacuum andthe residue was washed with Et₂O to give ethyl4-((2-ethoxy-3,4-dioxocyclobutyl)amino)benzoate (50 mg, 15%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ=11.0 (s, 1H), 7.93 (d, J=8.8 Hz,2H), 7.50 (d, J=8.8 Hz, 2H), 4.79 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz,2H), 1.42 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).

Step 2: A mixture of ethyl4-((2-ethoxy-3,4-dioxocyclobutyl)amino)benzoate (50 mg, 0.17 mmol) andpyridin-4-ylmethanamine (19 mg, 0.17 mmol) in EtOH (5.0 mL) was stirredat room temperature for 48 hrs. The mixture was concentrated in vacuumand the residue was purified by column chromatography on silica gel(DCM/MeOH=10/1) to give ethyl4-((2,3-dioxo-4-((pyridin-4-ylmethyl)amino)cyclobutyl)amino)benzoate (25mg, 42%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ=10.1 (s, 1H),8.57 (d, J=4.4 Hz, 2H), 8.21 (brs, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.54 (d,J=7.6 Hz, 2H), 7.40 (d, J=4.4 Hz, 2H), 4.87 (d, J=6.0 Hz, 2H), 4.28 (q,J=7.2 Hz, 2H), 1.31-1.29 (t, J=7.2 Hz, 3H). MS: m/z 351.9 (M+H⁺).

Example 366: Synthesis of Ethyl4-(2-amino-3-(pyridin-4-yl)propanamido)benzoate

Step 1: A mixture of 2-amino-3-(pyridin-4-yl)propanoic acid (332 mg, 2.0mmol), NaOH (160 mg, 4.0 mmol), Boc₂O (650 mg, 3.1 mmol) in t-BuOH (5mL) and H₂O (5 mL) was stirred at room temperature for 16 hrs. Themixture was concentrated in vacuum and the residue was purified by flashchromatography to give2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanoic acid (300 mg,56%) as a white solid.

Step 2: A mixture of2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanoic acid (150 mg,0.56 mmol), HATU (350 mg, 0.86 mmol) and DIEA (220 mg, 1.71 mmol) in DMF(5 mL) was stirred at room temperature for 16 hrs. The mixture wasconcentrated in vacuum and the residue was purified by flashchromatography to give ethyl4-(2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanamido)benzoate(60 mg, yield: 34%) as a white solid.

Step 3: A mixture of ethyl4-(2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanamido)benzoate(60 mg, 0.14 mmol) and HCl/dioxane (4 mL) in dioxane (5 mL) was stirredat room temperature for 1 hr. The mixture was concentrated in vacuum andthe residue was purified by prep-HPLC to give ethyl4-(2-amino-3-(pyridin-4-yl)propanamido)benzoate (5 mg, yield: 11%) as awhite solid. ¹H NMR (400 MHz, DMSO-d6): δ=8.41 (d, J=6.0 Hz, 2H), 7.95(d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.32 (d, J=6.0 Hz, 2H), 4.35(q, J=7.2 Hz, 2H), 3.76 (t, J=6.8 Hz, 1H), 3.16-3.11 (m, 1H), 2.97-2.92(m, 1H), 1.32 (t, J=7.2 Hz, 3H). MS: m/z 314.0 (M+H⁺).

Example 367: Synthesis of4-{[(Pyridin-4-ylmethyl)-carbamoyl]-methyl}-benzoic acid ethyl ester

Step 1: To a solution of (4-bromo-phenyl)-acetic acid (497 mg, 2.31mmol) in DMF (10 mL), was added 4-(aminomethyl)pyridine (293 mg, 2.72mmol) and DIPEA (1.9 mL, 10.9 mmol), HATU (1.266 g, 3.33 mmol). Themixture was stirred 2 hrs at room temperature. After that, water (50 mL)and EA (50 mL) was added. The aqueous phase was extracted with EA (50mL×2). The extracts were washed with brines (50 mL×2), dried over Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography (PE/EA=1/1) to give2-(4-bromo-phenyl)-N-pyridin-4-ylmethyl-acetamide (290 mg, yield: 42%)as a white solid.

Step 2: To a solution of2-(4-bromo-phenyl)-N-pyridin-4-ylmethyl-acetamide (290 mg, 0.95 mmol) inEtOH (10 mL), was added Pd(dppf)Cl₂ (145 mg, 0.198 mmol), and Et₃N (0.5mL, 3.6 mmol). The suspension was degassed and purged with CO forseveral times. The mixture was refluxed overnight. After that, themixture was filtered and the filtrate was purified by prep-HPLC to give4-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-benzoic acid ethyl ester (30mg, yield: 10%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.52 (d,J=6.0 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.09 (d,J=6.0 Hz, 2H), 5.79 (s, 1H), 4.42 (d, J=6.0 Hz, 2H), 4.38 (q, J=7.2 Hz,2H), 3.72 (s, 2H), 1.40 (t, J=7.2 Hz, 3H). MS: m/z 298.9 (M+H⁺).

Example 368: Synthesis of 4-(3-Pyridin-4-yl-propionylamino)-benzoic acidethyl ester

To a solution of 3-pyridin-4-yl-propionic acid (150 mg, 1.0 mmol) in DMF(5 mL), was added HATU (570.3 mg, 1.499 mmol) and DIPEA (1.0 mL, 5.7mmol), the mixture was stirred for half an hour at room temperature,followed by the addition of 4-amino-benzoic acid ethyl ester (225 mg,1.36 mmol). The mixture was stirred over night at room temperature.After that, water (20 mL×2) and EA (20 mL) was added. The aqueous phasewas extracted with EA (20 mL). The extracts were washed with brines (30mL×2), dried over Na₂SO₄ and concentrated to dryness. The residue waspurified by silica gel column chromatography (EA) to give4-(3-pyridin-4-yl-propionylamino)-benzoic acid ethyl ester (30 mg,yield: 10%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.30 (s,1H), 8.46 (d, J=5.6 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz,2H), 7.28 (d, J=5.6 Hz, 2H), 4.28 (q, J=6.8 Hz, 2H), 2.93 (t, J=7.6 Hz,2H), 2.72 (t, J=7.6 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H). MS: m/z 299.1(M+H⁺).

Example 369: Synthesis of Ethyl4-({(1E)-2-cyano-1-[(4-pyridylmethyl)amino]-2-azavinyl}amino)benzoate

Step 1: To a solution of cyanamide (3 g, 71.4 mmol) in methanol (30 mL)was added sodium methoxide (3.9 g, 72.2 mmol) in portions. After stirredat room temperature for 2 hrs, the mixture was evaporated in vacuum toafford crude sodium cyanmide as a white solid which was used for nextstep without further purification.

Step 2: To a suspension of 4-isothiocyanato-benzoic acid ethyl ester(200 mg, 0.98 mmol) in EtOH (10 mL) was added sodium cyanmide (62 mg,0.98 mmol). After heated to 70° C. overnight, the mixture was evaporatedin vacuum. The residue was purified by flash column chromatograph (ACNin water: 5% to 95%) to afford ethyl4-{[(cyanoamino)thioxomethyl]amino}benzoate (30 mg, 13%) as a whitesolid. ¹H NMR (400 MHz, CD₃OD): δ=7.89 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 4.32 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).

Step 3: To a solution of ethyl4-{[(cyanoamino)thioxomethyl]amino}benzoate (30 mg, 0.12 mmol) in DMF (5mL) was added 4-(aminomethyl)pyridine (15.7 mg, 0.14 mmol) and EDCI(27.8 mg, 0.14 mmol). After stirred at room temperature overnight, thereaction mixture was evaporated in vacuum. The residue was purified byprep-TLC (DCM/MeOH=10/1) to afford ethyl4-({(1E)-2-cyano-1-[(4-pyridylmethyl)amino]-2-azavinyl}amino)benzoate(20 mg, 51%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=8.50 (d,J=5.6 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.40-7.37 (m, 4H), 4.55 (s, 2H),4.35 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.0 Hz, 3H). MS: m/z 322.1 (M−H)⁻.

Example 370: Synthesis of4-{2-Nitro-1-[(pyridin-4-ylmethyl)-amino]-vinylamino}-benzoic acid ethylester

Step 1: To a solution of 4-amino-benzoic acid ethyl ester (2 g, 12.1mmol) in ethanol (200 mL) was added1,1-bis-methylsulfanyl-2-nitro-ethene (1.7 g, 12.1 mmol). After refluxfor 4 days, the mixture was concentrated in vacuum. The residue waspurified by flash column (ACN in water: 5% to 95%) to afford4-(1-methylsulfanyl-2-nitro-vinylamino)-benzoic acid ethyl ester (270mg, 8%) as a yellow solid. MS: m/z 280.9 (M−H)⁻.

Step 2: To a solution of 4-(1-methylsulfanyl-2-nitro-vinylamino)-benzoicacid ethyl ester (60 mg, 0.21 mmol) in methanol (10 mL) was addedPyridin-4-ylmethanamine (230 mg, 2.1 mmol). After stirred at roomtemperature overnight, the mixture was concentrated in vacuum. Theresidue was purified by prep-TLC (DCM/MeOH=10/1) to afford4-{2-nitro-1-[(pyridin-4-ylmethyl)-amino]-vinylamino}-benzoic acid ethylester (18.8 mg, 25.8%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD):δ=8.54 (d, J=6.4 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.42 (d, J=6.4 Hz,2H), 7.37 (d, J=8.0 Hz, 2H), 6.52 (s, 1H), 4.71 (s, 2H), 4.37 (q, J=7.2Hz, 2H), 1.38 (t, J=7.2 Hz, 3H). MS: m/z 343.0 (M+H)⁺.

Example 371: Synthesis of[6-(Morpholine-4-sulfonyl)-benzothiazol-2-yl]-pyridin-4-ylmethyl-amine

Step 1: To a solution of 3-fluoro-4-nitro-benzenesulfonyl chloride (1 g,4.2 mmol) in dry DCM (15 mL) was added TEA (402.4 mg, 4.6 mmol). Thenmorpholine (468 mg, 4.6 mmol) was added dropwise and the reactionmixture was stirred at room temperature overnight. Then the mixture wasconcentrated in vacuum. The residue was purified by silica gel columnchromatograph (PE:EA=2:1) to afford4-(3-fluoro-4-nitro-benzenesulfonyl)-morpholine (617 mg, 51.4%) as ayellow solid.

Step 2: To a solution of 4-(3-fluoro-4-nitro-benzenesulfonyl)-morpholine(600 mg, 2.1 mmol) in DMF (10 mL) was added Na₂S (803 mg, 10.3 mmol).After stirred at room temperature overnight, the reaction mixture wasadded 1M HCl to pH=6. Then the mixture was diluted in H₂O (50 mL) andextracted by EA (50 mL×3). Organic phase was combined and evaporated invacuum to afford 5-(morpholine-4-sulfonyl)-2-nitro-benzenethiol (600 mg,crude) as a yellow solid which was used for next step without furtherpurification.

Step 3: To a solution of 5-(morpholine-4-sulfonyl)-2-nitro-benzenethiol(600 mg, crude) in a mixture of EtOH (80 mL) and H₂O (20 mL) was addedFe powder (560 mg, 10 mmol), NH₄Cl (1.1 g, 20 mmol), and CDI (973.2 mg,6 mmol). After heated to reflux overnight, the reaction mixture wasfiltered. The filtrate was diluted in H₂O (100 mL) and extracted by EA(50 mL×3). Organic phase was combined and evaporated in vacuum. Theresidue was purified by flash column chromatograph (ACN in water: 10% to95%) to afford 6-(morpholine-4-sulfonyl)-3H-benzothiazol-2-one (200 mg,34%) as a yellow solid.

Step 4: 6-(Morpholine-4-sulfonyl)-3H-benzothiazol-2-one (40 mg, 0.13mmol) was dissolved in POCl₃ (10 mL). After stirred at reflux overnight,the reaction mixture was concentrated in vacuum. The residue waspartitioned in a mixture of EA (20 mL) and H₂O (20 mL). Then K₂CO₃powder was added to pH>7. Then organic phase was collected andevaporated in vacuum. The residue was purified by flash columnchromatograph (ACN in water: 10% to 95%) to afford2-chloro-6-(morpholine-4-sulfonyl)-benzothiazole (40 mg, 94.1%) as ayellow solid.

Step 5: To a solution of2-chloro-6-(morpholine-4-sulfonyl)-benzothiazole (20 mg, 0.063 mmol) indioxane (10 mL) was added Pyridin-4-ylmethanamine (13.6 mg, 0.126 mmol)and DIPEA (16.3 mg, 0.126 mmol). After stirred at reflux overnight, thereaction mixture was evaporated in vacuum. The residue was purified byprep-HPLC to afford[6-(morpholine-4-sulfonyl)-benzothiazol-2-yl]-pyridin-4-ylmethyl-amine(5.4 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=8.49 (d,J=6.4 Hz, 2H), 8.08 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.4, 2.0 Hz, 1H),7.54 (d, J=8.4 Hz, 1H), 7.45 (d, J=6.0 Hz, 2H), 4.78 (s, 2H), 3.71-3.68(m, 4H), 2.96-2.94 (m, 4H). MS: m/z 390.9 (M+H)⁺.

Example 372: Synthesis of1-(1-Phenylmethanesulfonyl-piperidin-4-yl)-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of piperidin-4-yl-carbamic acid tert-butyl ester(1.0 g, 5.0 mmol) and Et₃N (1.1 mL, 7.5 mmol) in DCM (30 mL) was addedphenyl-methanesulfonyl chloride (1.1 g, 6.0 mmol) at 0° C. Afterstirring at room temperature for 1 h, the reaction mixture was dilutedwith DCM (50 mL), washed with water (30 mL). The DCM solution was driedover Na₂SO₄ and concentrated. The residue was washed with (PE/EA=1/1) togive (1-phenylmethanesulfonyl-piperidin-4-yl)-carbamic acid tert-butylester (1.0 g, yield: 56%) as a white solid. ¹H NMR (400 MHz, CDCl₃):δ=7.40-7.37 (m, 5H), 4.46-4.36 (m, 1H), 4.22 (s, 2H), 3.60 (d, J=12.4Hz, 2H), 3.52-3.39 (m, 1H), 2.62 (t, J=11.6 Hz, 2H), 1.87 (d, J=12.4 Hz,2H), 1.43 (s, 9H), 1.37-1.26 (m, 2H).

Step 2: To a solution of(1-phenylmethanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester(1.0 g, 2.8 mmol) in DCM/MeOH (10 mL/3 mL) was added HCl/dioxane (6 M,10 mL). After stirring at room temperature for 2 hrs, the reactionmixture was concentrated. To the residue was added aq.NaOH (10%, 50 mL)and the mixture was extracted by EA (30 mL×4). The combined EA waswashed with brine, dried over Na₂SO₄ and concentrated to give1-phenylmethanesulfonyl-piperidin-4-ylamine (700 g, yield: 97%) as awhite solid.

Step 3: To a solution of 1-phenylmethanesulfonyl-piperidin-4-ylamine(250 mg, 1.0 mmol) in DCM/H₂O (20 mL/20 mL) was added NaHCO₃ (340 mg,4.0 mmol) and triphosgene (90 mg, 0.3 mmol) at 0° C. After stirring at0° C. for 30 min, organic layer was separated, dried over Na₂SO₄ andconcentrated to give 4-isocyanato-1-phenylmethanesulfonyl-piperidine(crude) as a white solid.

Step 4: To a solution of 4-isocyanato-1-phenylmethanesulfonyl-piperidine(crude) in MeCN (10 mL) was added pyridin-4-ylmethanamine (110 mg, 1.0mmol) at 0° C. After stirring at room temperature for 30 min, theprecipitation was collected and washed with MeCN (10 mL) to give1-(1-phenylmethanesulfonyl-piperidin-4-yl)-3-pyridin-4-ylmethyl-urea(300 mg, yield: 77%, two steps) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ=8.60 (d, J=6.0 Hz, 2H), 7.42-7.33 (m, 5H), 7.21 (d, J=6.0Hz, 2H), 6.38 (t, J=6.0 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 4.39 (s, 2H),4.22 (d, J=6.0 Hz, 2H), 3.51-3.45 (m, 3H), 2.80 (t, J=10.6 Hz, 2H), 1.79(dd, J=12.8, 2.8 Hz, 2H), 1.35-1.24 (m, 2H). MS: m/z 389.0 (M+H⁺).

Example 373: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea

Step 1: To a solution of 2-fluorobenzenethiol (384.5 mg, 3.0 mmol) inDMF (20 mL) was added 1-chloro-4-nitrobenzene (709 mg, 4.5 mmol) andfollowed by K₂CO₃ (1.24 g, 9.0 mmol). The resulting mixture was stirredat 80° C. overnight. The reaction was monitored by TLC. Then K₂CO₃ wasremoved by filtration. The filtrate was concentrated in vacuum. Theresidue was purified by silica gel column (PE/EA=100/1 as eluent) toafford (2-fluorophenyl)(4-nitrophenyl)sulfane (596 mg, yield 80%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.11-8.06 (m, 2H), 7.60-7.54(m, 1H), 7.53-7.46 (m, 1H), 7.28-7.22 (m, 2H), 7.21-7.17 (m, 2H).

Step 2: To a solution of (2-fluorophenyl)(4-nitrophenyl)sulfane (596 mg,2.39 mmol) in DCM (30 mL) was added m-CPBA (1.77 g, 7.17 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. Then the mixture was mixture withsaturated Na₂SO₃ and extracted with DCM (20 mL×2). The combined organiclayer was concentrated in vacuum. The residue was purified by silica gelcolumn (PE/EA=10/1) to afford1-fluoro-2-((4-nitrophenyl)sulfonyl)benzene (608 mg, yield: 90%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ=8.40-8.33 (m, 2H), 8.24-8.17 (m,2H), 8.16-8.11 (m, 1H), 7.69-7.62 (m, 1H), 7.41-7.35 (m, 1H), 7.18-7.11(m, 1H).

Step 3: To a suspension of 1-fluoro-2-((4-nitrophenyl)sulfonyl)benzene(608 mg, 2.16 mmol) in MeOH (20 mL) was added Pd/C (60 mg, 10% wt). Theresulting mixture was stirred under H₂ (balloon) atmosphere at roomtemperature for 4 hrs. The reaction was monitored by LC-MS and TLC. ThenPd/C was removed by filtration. The filtrate was concentrated in vacuumto give 4-((2-fluorophenyl)sulfonyl)aniline (412 mg, yield 76%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.93 (dt, J=8.0, 2.0 Hz, 1H),7.73-7.65 (m, 1H), 7.55 (dd, J=8.8, 0.8 Hz, 2H), 7.41 (dt, J=8.8, 0.8Hz, 1H), 7.39-7.32 (m, 1H), 6.67-6.60 (m, 2H), 6.26 (brs, 2H).

Step 4: To a solution of 4-((2-fluorophenyl)sulfonyl)aniline (250 mg,1.0 mmol) in dry DCM (20 mL) was added phenyl chloroformate (236 mg,1.50 mmol), followed by TEA (303.6 mg, 3.0 mmol). The resulting mixturewas stirred at room temperature for 1 hr. The reaction was monitored byTLC. Then the mixture was concentrated in vacuum. The residue waspurified by silica gel column (PE/EA=10/1) to afford phenyl(4-((2-fluorophenyl)sulfonyl)phenyl)carbamate (252.6 mg, yield 68%) as awhite solid.

Step 5: To a solution of (4-((2-fluorophenyl)sulfonyl)phenyl)carbamate(252.6 mg, 0.68 mmol) in ACN (40 mL) was added(1H-pyrazol-4-yl)methanamine (200 mg, 2.06 mmol), followed by TEA (206mg, 2.04 mmol). The resulting mixture was stirred at 80° C. for 2 hrs.The reaction was monitored by LC-MS. Then the mixture was concentratedin vacuum. The residue was purified by prep-HPLC with NH₄OH as additiveto afford1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea(83.8 mg, yield 33%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=12.63 (br s, 1H), 9.07 (s, 1H), 8.04-7.96 (m, 1H), 7.83-7.49 (m, 7H),7.46 (t, J=6.8 Hz, 1H), 7.39 (t, J=9.2 Hz, 1H), 6.57 (t, J=5.6 Hz, 1H),4.15 (d, J=5.2 Hz, 2H). MS: m/z 374.9 (M+H⁺).

Example 374: Synthesis of1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.41 (br s, 1H), 8.49 (d, J=5.6 Hz, 2H),8.01 (dt, J=8.8, 1.6 Hz, 1H), 7.84-7.71 (m, 3H), 7.65 (d, J=8.8 Hz, 2H),7.46 (t, J=7.6 Hz, 1H), 7.40 (t, J=9.2 Hz, 1H), 7.28 (d, J=6.0 Hz, 2H),7.01 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 385.9 (M+H⁺).

Example 375: Synthesis of1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepare using genera procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.33 (br s, 1H), 8.28 (s, 1H), 8.00 (dt,J=8.0, 1.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.79-7.71 (m, 1H), 7.64 (d,J=8.8 Hz, 2H), 7.46 (t, J=7.2 Hz, 1H), 7.40 (t, J=9.6 Hz, 1H), 7.01 (s,1H), 6.97 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 375.9(M+H⁺).

Example 376: Synthesis of1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.39 (br s, 1H), 8.49 (dd, J=4.4, 1.6 Hz,2H), 7.85 (d, J=9.2 Hz, 2H), 7.79-7.73 (m, 2H), 7.71-7.60 (m, 3H),7.58-7.50 (m, 1H), 7.27 (d, J=5.6 Hz, 2H), 7.01 (t, J=6.0 Hz, 1H), 4.33(d, J=6.0 Hz, 2H). MS: m/z 385.9 (M+H⁺).

Example 377: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-fluorophenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (br s, 1H), 9.04 (s, 1H), 7.88-7.81(m, 2H), 7.78-7.72 (m, 2H), 7.69-7.64 (m, 1H), 7.64-7.58 (m, 2H),7.58-7.44 (m, 3H), 6.57 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H). MS:m/z 375.0 (M+H⁺).

Example 378: Synthesis of1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.22 (br s, 1H), 8.29 (s, 1H), 7.85 (d,J=8.8 Hz, 2H), 7.80-7.73 (m, 2H), 7.71-7.59 (m, 3H), 7.58-7.51 (m, 1H),7.01 (s, 1H), 6.87 (t, J=6.0 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H). MS: m/z375.9 (M+H⁺).

Example 379: Synthesis of1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.33 (br s, 1H), 8.49 (d, J=5.6 Hz, 2H),7.98 (dd, J=8.8, 4.8 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz,2H), 7.44 (t, J=8.8 Hz, 2H), 7.27 (d, J=5.6 Hz, 2H), 6.96 (t, J=6.0 Hz,1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 385.9 (M+H⁺).

Example 380: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-fluorophenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (br s, 1H), 9.01 (s, 1H), 8.02-7.94(m, 2H), 7.84-7.78 (m, 2H), 7.63-7.58 (m, 2H), 7.57-7.47 (m, 2H),7.46-7.40 (m, 2H), 6.55 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H). MS:m/z 374.9 (M+H⁺).

Example 381: Synthesis of1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.18 (br s, 1H), 8.28 (s, 1H), 8.02-7.94(m, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.61 (d, J=9.2 Hz, 2H), 7.44 (t, J=8.8Hz, 2H), 7.00 (s, 1H), 6.85 (t, J=6.0 Hz, 1H), 4.37 (d, J=6.0 Hz, 2H).MS: m/z 375.9 (M+H⁺).

Example 382: Synthesis of1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.23 (s, 1H), 8.28 (s, 1H), 8.23 (d, J=7.6Hz, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.37-7.57 (m, 5H), 7.01 (s, 1H), 6.86(t, J=6.0 Hz, 1H). MS: m/z 391.9 (M+H⁺).

Example 383: Synthesis of1-(4-((3-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.22 (brs, 1H), 8.28 (s, 1H), 7.94 (t,J=1.6 Hz, 1H), 7.89-7.83 (m, 3H), 7.77-7.72 (m, 1H), 7.66-7.58 (m, 3H),7.01 (s, 1H), 6.87 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z391.9 (M+H⁺).

Example 384: Synthesis of1-(4-((4-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.23 (brs, 1H), 8.28 (s, 1H), 7.94-7.88 (m,2H), 7.82 (d, J=8.8 Hz, 2H), 7.70-7.65 (m, 2H), 7.64-7.58 (m, 2H), 7.01(s, 1H), 6.88 (t, J=6.0 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z 391.9(M+H⁺).

Example 385: Synthesis of1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3-amino-benzenethiol (1.25 g, 10 mmol) in DMF(30 mL) was added 1-fluoro-4-nitro-benzene (1.69 g, 12 mmol), followedby K₂CO₃ (2.76 g, 20 mmol). The resulting mixture was stirred at 80° C.overnight. The reaction was monitored by TLC and LC-MS. Aftercompletion, the reaction mixture was filtered. The cake was washed withMeOH (20 mL) and dried in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=5/1) to afford3-(4-nitro-phenylsulfanyl)-phenylamine (1.95 g, yield: 81%) as an orangesolid.

Step 2: To a solution of 3-(4-nitro-phenylsulfanyl)-phenylamine (1.0 g,4.0 mmol) in a mixture solvents of aqueous 30% H₂SO₄ (10 mL) and DMSO(10 mL) was added aqueous NaNO₂ (828 mg, 12 mmol) in H₂O (2 mL). Theresulting mixture was stirred at 5° C. for 0.5 hr. Then aqueous KI (3.98g, 24 mmol) in H₂O (2 mL) was added into the reaction mixture, and theresulting mixture was stirred at room temperature for 5 hrs. Thereaction was monitored by LC-MS and TLC. After completion, the mixturewas poured into water (10 mL) and extracted with EA (5 mL×4). Thecombined organic layers were washed with saturated NaSO₃ (10 mL), driedover anhydrous sodium sulfate and concentrated in vacuum to give aresidue, which was purified by a silica gel column (PE/EA=5/1) to afford(3-iodophenyl)(4-nitrophenyl)sulfane (1 g, yield: 72%) as a yellowsolid.

Step 3: To a solution of (3-iodophenyl)(4-nitrophenyl)sulfane (1 g, 2.8mmol) in DMF (20 mL) was added m-CPBA (963 mg, 5.6 mmol). The resultingmixture was stirred at room temperature overnight. The reaction wasmonitored by TLC and LC-MS. After completion, the mixture was pouredinto saturated NaSO₃ (10 mL) and extracted with EA (5 mL×4). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuum to give a residue, which was purified by a silicagel column eluting with PE/EA=6/1 toafford1-iodo-3-((4-nitrophenyl)sulfonyl)benzene (630 mg, yield: 63%) asa brown solid.

Step 4: To a mixture of 1-iodo-3-((4-nitrophenyl)sulfonyl)benzene (630mg, 1.6 mmol) in EtOH/H₂O (30 mL, 5/1) was added iron (454 mg, 8.1 mmol)and NH₄Cl (429 mg, 8.1 mmol). The resulting mixture was stirred at 80°C. overnight. The reaction was monitored by LC-MS. After completion, thereaction mixture was filtered and the cake was rinsed with DCM/MeOH (100mL, 10/1). The combined filtrate was dried in vacuum to give a residue,which was purified by a silica gel column eluting with DCM to afford4-((3-iodophenyl)sulfonyl)aniline (630 mg, yield: 70%) as white solid.¹H NMR (400 MHz, DMSO-d₆): δ=8.09 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.83(d, J=8.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.35 (t, J=8.0 Hz, 1H), 6.62(d, J=8.8 Hz, 2H), 6.241 (brs, 2H).

Step 5: To a solution of 4-((3-iodophenyl)sulfonyl)aniline (100 mg, 0.28mmol) in DCM (30 mL) was added phenyl chloroformate (87 mg, 0.58 mmol)and TEA (84 mg, 0.84 mmol). The resulting mixture was stirred at roomtemperature for 1 hr. The reaction was monitored by TLC. Aftercompletion, DCM was removed in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=6/1) to afford[4-(3-iodo-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (130 mg,yield: 97%) as a yellow solid.

Step 6: To a solution of [4-(3-iodo-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (130 mg, 0.27 mmol) in ACN (20 mL) was addedC-pyridin-4-yl-methylamine (34 mg, 0.33 mmol) and TEA (0.5 ml). Theresulting mixture was stirred at 80° C. for 4 hr. The reaction wasmonitored by TLC and LCMS. After completion, the reaction mixture wasconcentrated in vacuum to give a residue, which was purified by prep-TLC(DCM/MeOH=20/1) to afford1-[4-(3-iodo-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (130 mg,yield: 98%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.34 (d, 1H),8.50-8.48 (m, 2H), 8.17 (t, J=1.6 Hz, 1H), 8.03-8.01 (m, 1H), 7.91-7.89(m, 1H), 7.83 (d, J=9.2 Hz, 2H), 7.63 (d, J=6.8 Hz, 2H), 7.38 (t, J=8.0Hz, 1H), 7.27 (d, J=6.0 Hz, 2H), 6.96 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0Hz, 2H). MS: m/z 493.6 (M+H⁺).

Example 386: Synthesis of1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(3-iodo-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹H NMR(400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.04 (brs, 1H), 8.18-8.17 (m,1H), 8.02 (d, J=8.0 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.83 (d, J=8.8 Hz,2H), 7.61 (d, J=9.2 Hz, 2H), 7.53 (brs, 2H), 7.38 (t, J=8.0 Hz, 1H),6.56 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 482.6 (M+H⁺).

Example 387: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=8.46 (d, J=6.0 Hz, 2H), 8.13 (d, J=8.0 Hz,1H), 7.45 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H) 7.55-7.50 (m, 1H),7.45-7.41 (m, 1H), 7.38 (d, J=6.0 Hz, 2H), 7.31 (d, J=7.2 Hz, 1H), 4.45(s, 2H), 2.42 (s, 3H), MS: m/z 381.8 (M+H⁺).

Example 388: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=8.13 (d, J=7.6 Hz, 1H), 7.73 (d, J=8.4 Hz,2H), 7.60-7.51 (m, 5H), 7.45-7.41 (m, 1H), 7.30 (d, J=7.2 Hz, 1H), 4.28(s, 2H), 2.41 (s, 3H). MS: m/z 370.8 (M+H⁺).

Example 389: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=8.12-8.10 (m, 2H), 7.73 (d, J=8.8 Hz, 2H),7.59 (d, J=8.8 Hz, 2H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.31 (d,J=7.6 Hz, 1H), 7.02 (s, 1H), 4.46 (s, 2H), 2.42 (s, 3H). MS: m/z 371.9(M+H⁺).

Example 390: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.85 (s, 1H), 8.49-8.47 (m, 2H), 7.81 (d,J=8.8 Hz, 2H), 7.71 (s, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.48 (d, J=6.4 Hz,2H), 7.28 (d, J=6.0 Hz, 2H), 4.34 (d, J=5.6 Hz, 2H), 2.31 (s, 3H). MS:m/z 382.0 (M+H⁺).

Example 391: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-3-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=7.81 (d, J=9.2 Hz, 2H), 7.72 (d, J=6.8 Hz,2H), 7.58-7.55 (m, 4H), 7.43 (d, J=4.8 Hz, 2H), 4.28 (s, 2H), 2.39 (s,3H). MS: m/z 370.9 (M+H⁺).

Example 392: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.76 (br s, 1H), 8.28 (s, 1H), 7.80 (d,J=8.8 Hz, 2H), 7.71-7.67 (m, 2H), 7.62 (d, J=9.2 Hz, 2H), 7.48 (d, J=7.2Hz, 2H), 7.19 (s, 1H), 7.00 (s, 1H), 4.37 (d, J=5.6 Hz, 2H), 2.37 (s,3H). MS: m/z 371.9 (M+H⁺).

Example 393: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=8.47-8.45 (m, 2H), 7.81-7.78 (m, 4H),7.60-7.57 (m, 2H), 7.39-7.35 (m, 4H), 4.44 (s, 2H), 2.39 (s, 3H). MS:m/z 381.9 (M+H⁺).

Example 394: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-4-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=7.80-7.78 (m, 4H), 7.65-7.50 (m, 4H), 7.36(d, J=8.4 Hz, 2H), 4.28 (s, 2H), 2.39 (s, 3H). MS: m/z 371.0 (M+H⁺).

Example 395: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, CD₃OD): δ=8.13 (s, 1H), 7.81-7.78 (m, 4H), 7.57 (d,J=8.8 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.02 (s, 1H), 4.46 (s, 2H), 2.39(s, 3H). MS: m/z 371.9 (M+H⁺).

Example 396: Synthesis of1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 4-mercapto-benzonitrile (900 mg, 6.65 mmol) inDMF (30 mL) was added 1-chloro-4-nitro-benzene (1.577 g, 9.9 mmol) andK₂CO₃ (4.6 g, 33.282 mmol). The reaction mixture was stirred at 80° C.under N₂ overnight. The reaction was completed detected by LC-MS. Thereaction was quenched with water (40 mL) and extracted with EA (40mL×3). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash column(PE/EA=40/1) to give 4-(4-nitro-phenylsulfanyl)-benzonitrile (1.579 g,yield: 93%) as a yellow solid.

Step 2: To a solution of 4-(4-nitro-phenylsulfanyl)-benzonitrile (1 g,3.9 mmol) in DCM (20 mL) was added m-CPBA (2.88 g, 11.7 mmol, 70% Wt) atroom temperature. The solution was stirred at room temperatureovernight. The reaction was completed detected by TLC. The reaction wasquenched with Na₂SO₃ aqueous (10 mL) and extracted with DCM (20 mL×3).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (PE toPE/EA=50/1) to give 4-(4-nitro-benzenesulfonyl)-benzonitrile (1.15 g,yield: 100%) as a white solid.

Step 3: To a solution of 4-(4-nitro-benzenesulfonyl)-benzonitrile (1.15g, 3.9 mmol) in EtOH (60 mL) and H₂O (15 mL) was added Fe (1.089 g, 19.5mmol) and NH₄Cl (1.044 g, 19.5 mmol). The reaction mixture was stirredat 80° C. under N₂ overnight. The reaction was completed detected byLC-MS. After filtration via filter paper, the organic layer wasconcentrated under pressure to give4-(4-amino-benzenesulfonyl)-benzonitrile (0.985 g, yield: 98%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.05-7.99 (m, 4H), 7.58 (d,J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 6.32 (s, 2H).

Step 4: To a solution of 4-(4-amino-benzenesulfonyl)-benzonitrile (0.985g, 3.81 mmol) in DCM (60 mL) was added pyridine (1.54 g, 15.25 mmol) andphenyl chloroformate (1.193 g, 7.63 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 2 hrs. The reaction was completeddetected by TLC. The reaction was concentrated and purified by flashcolumn (PE/EA=2/1) to give [4-(4-cyano-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (0.826 g, yield: 57%) as a white solid. ¹H NMR (400MHz, CDCl₃): δ=8.10-8.06 (m, 4H), 7.82 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.37 (d, J=8.0 Hz, 3H), 7.11 (d, J=7.6 Hz, 3H).

Step 5: To a solution of [4-(4-cyano-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (150 mg, 0.397 mmol) in ACN (10 mL) was added TEA (120mg, 0.595 mmol) and c-pyridin-4-yl-methylamine (64.3 mg, 0.595 mmol).The reaction mixture was stirred at 80° C. for 5 hrs. The reaction wascompleted detected by LC-MS. The reaction was concentrated and purifiedby prep-HPLC (5-95; NH₄HCO₃) to give1-[4-(4-cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (25 mg,yield: 16%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.39 (s, 1H),8.50-8.49 (m, 2H), 8.08 (s, 4H), 7.86 (d, J=9.2 Hz, 2H), 7.64 (d, J=9.2Hz, 2H), 7.27 (d, J=6.0 Hz, 2H), 6.99 (t, J=5.6 Hz, 1H), 4.33 (d, J=6.0Hz, 2H). MS: m/z 392.9 (M+H⁺).

Example 397: Synthesis of1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(4-cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹H NMR(400 MHz, CD₃OD): δ=7.99 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.76(d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 4H), 4.18 (s, 2H). MS: m/z 381.9(M+H⁺).

Example 398: Synthesis of1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(4-cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹H NMR(400 MHz, DMSO-d₆): δ=9.78-9.74 (m, 1H), 8.28 (s, 1H), 8.07 (s, 4H),7.85 (d, J=9.2 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.17 (s, 1H), 7.00 (s,1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z 382.9 (M+H⁺).

Example 399: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

Step 1: To a solution of 2-trifluoromethyl-benzenethiol (534.51 mg, 3.0mmol) in DMF (20 mL) was added 1-fluoro-4-nitro-benzene (635.0 mg, 4.5mmol) and K₂CO₃ (1.24 g, 9.0 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=50/1) to afford3-(4-nitro-phenylsulfanyl)-2-trifluoromethyl-benzenee (940 mg,yield: >100%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.16 (d,J=9.2 Hz, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.84-7.71 (m, 3H), 7.30 (d, J=8.8Hz, 2H).

Step 2: To a solution of3-(4-nitro-phenylsulfanyl)-2-trifluoromethyl-benzenee (940 mg, 3.14mmol) in DCM (50 mL) was added m-CPBA (1625.5 mg, 9.42 mmol), themixture was stirred at room temperature overnight. The reaction wasmonitored by TLC. After completion, the mixture was quenched withsaturated aqueous sodium sulfite. The organic layer was concentrated invacuum to give a residue, which was purified by a silica gel column(PE/EA=5/1) to afford3-(4-nitro-benzenesulfonyl)-2-trifluoromethyl-benzene (810 mg, 78%) as awhite solid.

Step 3: To a solution of3-(4-nitro-benzenesulfonyl)-2-trifluoromethyl-benzene (810 mg, 2.4 mmol)in MeOH (30 mL) was added Pd/C (10% wet, 93.6 mg). The reaction mixturewas stirred at room temperature under H₂ (1 atm) overnight. Pd/C wasfiltered off and the filtrate was concentrated to dryness in vacuum. Theresidue was purified by flash to give4-(2-trifluoromethyl-benzenesulfonyl)-phenylamine (528.3 mg, yield:71.1%) as a white solid.

Step 4: To a solution of4-(2-trifluoromethyl-benzenesulfonyl)-phenylamine (170 mg, 0.56 mmol) inDCM (30 mL) was added phenyl chloroformate (175.35 mg, 1.12 mmol) andTEA (113.34 mg, 1.12 mmol), the mixture was stirred at 0° C. for 1 hr.The reaction was monitored by TLC. After completion, the mixture wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=3/1) to afford[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-carbamic acid phenylester (220 mg, 92.6%) as a white solid.

Step 5: To a solution of[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-carbamic acid phenylester (50 mg, 0.12 mmol) in ACN (20 mL) was addedc-pyridin-4-yl-methylamine (25.92 mg, 0.24 mmol) and TEA (24.29 mg, 0.24mmol), the mixture was stirred at 80° C. for 3 hrs. The reaction wasmonitored by LCMS. After completion, the mixture was concentrated invacuum to give a residue, which was purified by prep-HPLC to give1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea(16.1 mg, yield: 31.1%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.38 (s, 1H), 8.49 (d, J=6.0 Hz, 2H), 8.33 (d, J=7.2 Hz, 1H),8.01-7.90 (m, 3H), 7.74 (d, J=8.8 Hz, 2H), 7.62 (d, J=9.2 Hz, 2H), 7.27(d, J=6.0 Hz, 2H), 6.96 (t, J=5.6 Hz, 1H), 4.33 (d, J=6.4 Hz, 2H). MS:m/z 435.9 (M+H⁺).

Example 400: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d6): δ=12.62 (s, 1H), 9.06 (s, 1H), 8.32 (d, J=7.6Hz, 1H), 8.02-7.86 (m, 3H), 7.73 (d, J=9.2 Hz, 2H), 7.60 (d, J=9.2 Hz,2H), 7.58-7.42 (m, 2H), 6.58 (t, J=5.2 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H).MS: m/z 424.9 (M+H⁺).

Example 401: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.76 (s, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.28(s, 1H), 8.02-7.87 (m, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.8 Hz,2H), 7.18 (t, J=5.2 Hz, 1H), 7.01 (s, 1H), 4.37 (d, J=5.6 Hz, 2H). MS:m/z 425.9 (M+H⁺).

Example 402: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.37 (br s, 1H), 8.49 (d, J=5.6 Hz, 2H),8.23 (d, J=8.0 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.95-7.82(m, 3H), 7.65 (d, J=8.8 Hz, 2H), 7.27 (d, J=6.0 Hz, 2H), 6.98 (t, J=5.6Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 435.9 (M+H⁺).

Example 403: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (br s, 1H), 9.06 (s, 1H), 8.23 (d,J=8.0 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93-7.83 (m, 3H),7.62 (d, J=9.2 Hz, 2H), 7.60-7.41 (m, 2H), 6.58 (t, J=5.6 Hz, 1H), 4.15(d, J=5.6 Hz, 2H). MS: m/z 424.9 (M+H⁺).

Example 404: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (br s, 1H), 8.28 (s, 1H), 8.23 (d,J=8.4 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.95-7.83 (m, 3H),7.63 (d, J=9.2 Hz, 2H), 7.01 (s, 1H), 6.90 (t, J=5.6 Hz, 1H), 4.37 (d,J=5.2 Hz, 2H). MS: m/z 425.9 (M+H⁺).

Example 405: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.38 (br s, 1H), 8.50 (dd, J=4.8, 1.6 Hz,2H), 8.12 (d, J=8.0 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.8 Hz,2H), 7.65 (d, J=8.8 Hz, 2H), 7.27 (d, J=6.0 Hz, 2H), 6.98 (t, J=5.6 Hz,1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 435.9 (M+H⁺).

Example 406: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (br s, 1H), 9.10 (s, 1H), 8.15 (d,J=8.4 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.84 (d, J=9.2 Hz, 2H), 7.62 (d,J=9.2 Hz, 2H), 7.59-7.37 (m, 2H), 6.59 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6Hz, 2H). MS: m/z 424.9 (M+H⁺).

Example 407: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.24 (br s, 1H), 8.28 (s, 1H), 8.12 (d,J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 7.64 (d,J=8.8 Hz, 2H), 7.01 (s, 1H), 6.88 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz,2H). MS: m/z 425.9 (M+H⁺).

Example 408: Synthesis of1-(4-((2-Methoxyphenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.14 (brs, 1H), 8.28 (s, 1H), 7.96 (dd,J=8.4, 1.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.64 (t, J=8.4 Hz, 1H), 7.57(d, J=8.8 Hz, 2H), 7.15 (t, J=8.0 Hz, 2H), 7.01 (s, 1H), 6.83 (t, J=5.6Hz, 1H), 4.37 (d, J=5.6 Hz, 2H), 3.75 (s, 3H). MS: m/z 387.9 (M+H⁺).

Example 409: Synthesis of1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

Step 1: To a solution of 3-methoxy-benzenethiol (420.6 mg, 3.0 mmol) inDMF (20 mL) was added 1-fluoro-4-nitro-benzene (635.0 mg, 4.5 mmol) andK₂CO₃ (1.24 g, 9.0 mmol), the mixture was stirred at 80° C. overnight.The reaction was monitored by TLC. After completion, the mixture wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=30/1) to afford1-methoxy-3-(4-nitro-phenylsulfanyl)-benzene (710 mg, yield: 90.5%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.15 (d, J=9.2 Hz, 2H), 7.46(t, J=8.0 Hz, 2H), 7.32 (d, J=9.2 Hz, 2H), 7.16-7.09 (m, 3H), 3.78 (s,3H).

Step 2: To a solution of 1-methoxy-3-(4-nitro-phenylsulfanyl)-benzene(710 mg, 2.72 mmol) in DCM (50 mL) was added m-CPBA (1.41 mg, 8.16mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite, the organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=10/1) to afford1-methoxy-3-(4-nitro-benzenesulfonyl)-benzene (0.71 g, 89.2%) as a whitesolid.

Step 3: To a solution of 1-methoxy-3-(4-nitro-benzenesulfonyl)-benzene(250 mg, 0.85 mmol) in MeOH (20 mL) was added Pd/C (10% wet, 30 mg), thereaction mixture was stirred at room temperature under H₂ (1 atm)overnight. Pd/C was filtered off and the filtrate was concentrated todryness in vacuum. The residue was purified by flash to give4-(3-methoxy-benzenesulfonyl)-phenylamine (210 mg, yield: 93.6%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.55 (d, J=8.8 Hz, 2H), 7.47(t, J=8.0 Hz, 1H), 7.40-7.35 (m, 1H), 7.31-7.28 (m, 1H), 7.19-7.14 (m,1H), 6.60 (d, J=8.8 Hz, 2H), 6.19 (s, 2H), 3.80 (s, 3H).

Step 4: To a solution of 4-(3-methoxy-benzenesulfonyl)-phenylamine (210mg, 0.79 mmol) in DCM (30 mL) was added phenyl chloroformate (247.38 mg,1.58 mmol) and TEA (159.58 mg, 1.58 mmol), the mixture was stirred at 0°C. for 1 hr. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=3/1) to afford[4-(3-methoxy-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (290mg, 94%) as a white solid.

Step 5: To a solution of [4-(3-methoxy-benzenesulfonyl)-phenyl]-carbamicacid phenyl ester (80 mg, 0.21 mmol) in ACN (25 mL) was addedc-oxazol-5-yl-methylamine (56.52 mg, 0.42 mmol) and TEA (42.5 mg, 0.42mmol), the mixture was stirred at 80° C. overnight. The reaction wasmonitored by LCMS. After completion, the mixture was concentrated invacuum to give a residue, the residue was purified by prep-HPLC to give1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea (12.1mg, yield: 14.9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.19(s, 1H), 8.28 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H),7.51 (t, J=7.6 Hz, 1H), 7.46-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.24-7.19(m, 1H), 7.00 (s, 1H), 6.86 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H),3.81 (s, 3H). MS: m/z 388.1 (M+H⁺).

Example 410: Synthesis of1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.14 (s, 1H), 8.28 (s, 1H), 7.82 (d, J=8.8Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.10 (d, J=9.2Hz, 2H), 7.00 (s, 1H), 6.83 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H),3.81 (s, 3H). MS: m/z 387.9 (M+H⁺).

Example 411: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.47-8.45 (m, 2H), 8.22 (d, J=1.2 Hz, 1H),7.82-7.79 (m, 2H), 7.79-7.75 (m, 1H), 7.63-7.56 (m, 3H), 7.40-7.35 (m,3H), 4.45 (s, 2H). MS: m/z 451.9 (M+H⁺).

Example 412: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.24-8.22 (m, 1H), 7.80-7.67 (m, 5H), 7.60-7.54(m, 3H), 7.43 (d, J=9.2 Hz, 1H), 4.29 (s, 2H). MS: m/z 440.9 (M+H⁺).

Example 413: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.23 (dd, J=8 Hz, 1.6 Hz, 1H), 8.13 (s, 1H),7.81-7.79 (m, 2H), 7.75-7.71 (m, 1H), 7.63-7.57 (m, 2H), 7.57-7.53 (m,1H), 7.42-7.40 (m, 1H), 7.04 (s, 1H), 4.47 (s, 2H). MS: m/z 441.9(M+H⁺).

Example 414: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.46 (d, J=5.6 Hz, 2H), 7.93-7.81 (m, 4H),7.69-7.61 (m, 3H), 7.55 (d, J=8.4 Hz, 1H), 7.38 (d, J=5.6 Hz, 2H), 4.44(s, 2H). MS: m/z 451.9 (M+H⁺).

Example 415: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=7.93-7.90 (m, 1H), 7.87-7.80 (m, 5H), 7.69-7.65(m, 1H), 7.62-7.55 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 4.31 (s, 2H). MS:m/z 440.9 (M+H⁺).

Example 416: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.13 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.86 (d,J=8.8 Hz, 2H), 7.81 (s, 1H), 7.69-7.65 (m, 1H), 7.62 (d, J=8.8 Hz, 2H),7.55 (d, J=8.4 Hz, 1H), 7.02 (s, 1H), 4.46 (s, 2H). MS: m/z 441.9(M+H⁺).

Example 417: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.46 (d, J=4.8 Hz, 2H), 8.04 (dd, J=6.8, 2.0 Hz,2H), 7.84 (dd, J=6.8, 2.0 Hz, 2H), 7.62 (dd, J=7.2, 1.6 Hz, 2H), 7.46(d, J=8.4 Hz, 2H), 7.38 (d, J=6.0 Hz, 2H) 4.44 (s, 2H). MS: m/z 451.7(M+H⁺).

Example 418: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.04 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H),7.63-7.58 (m, 4H), 7.46 (d, J=8.4 Hz, 2H), 4.28 (s, 2H). MS: m/z 440.7(M+H⁺).

Example 419: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(3-methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.13 (s, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.85 (d,J=9.2 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.02 (s,1H), 7.02 (s, 2H), 4.46 (s, 2H). MS: m/z 441.9 (M+H⁺).

Example 420: Synthesis of1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 2,4-difluoro-benzenethiol (584.6 mg, 4.0 mmol)in DMF (30 mL) was added 1-fluoro-4-nitro-benzene (846.59 mg, 6.0 mmol)and K₂CO₃ (1.66 g, 12.0 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=50/1) to afford2,4-difluoro-1-(4-nitro-phenylsulfanyl)-benzene (961 mg, yield: 91.3%)as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.09 (d, J=8.8 Hz, 2H),7.67-7.55 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.05-6.96 (m, 2H).

Step 2: To a solution of 2,4-difluoro-1-(4-nitro-phenylsulfanyl)-benzene(961 mg, 3.59 mmol) in DCM (40 mL) was added m-CPBA (2186.4 mg, 10.77mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite, the organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE:EA=10:1) to afford2,4-difluoro-1-(4-nitro-benzenesulfonyl)-benzene (961 mg, 89.3%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ=8.38 (d, J=8.8 Hz, 2H), 8.19 (d,J=9.2 Hz, 2H), 8.18-8.10 (m, 1H), 7.15-7.07 (m, 1H), 6.94-6.86 (m, 1H).

Step 3: To a solution of1,3-difluoro-5-(4-nitro-benzenesulfonyl)-benzene (300 mg, 1.0 mmol) inMeOH (30 mL), was added Pd/C (10% wet, 30 mg). The reaction mixture wasstirred at room temperature under H₂ (1 atm) overnight. Pd/C wasfiltered off and the filtrate was concentrated to dryness in vacuum. Theresidue was purified by flash to give4-(2,4-dfluoro-benzenesulfonyl)-phenylamine (215 mg, yield: 79.7%) as awhite solid.

Step 4: To a solution of 4-(2,4-dfluoro-benzenesulfonyl)-phenylamine(215 mg, 0.79 mmol) in DCM (40 mL) was added phenyl chloroformate (247.4mg, 1.58 mmol) and TEA (159.89 mg, 1.58 mmol), the mixture was stirredat 0° C. for 1 hr. The reaction was monitored by TLC. After completion,the mixture was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(302 mg, yield: 97%) as a white solid.

Step 5: To a solution of[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (50mg, 0.13 mmol) in ACN (30 mL) was added c-pyridin-4-yl-methylamine(28.12 mg, 0.26 mmol) and TEA (26.31 mg, 0.26 mmol), the mixture wasstirred at 80° C. for 3 hrs. The reaction was monitored by LCMS. Aftercompletion, the mixture was concentrated in vacuum to give a residue,the residue was purified by prep-HPLC to give1-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea (8mg, yield: 1.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=10.23 (s,1H), 8.49 (J=6.0 Hz, 2H), 8.12-8.03 (m, 1H), 8.79 (d, J=8.4 Hz, 2H),7.66 (d, J=8.8 Hz, 2H), 7.62-7.46 (m, 2H), 7.40-7.33 (m, 1H), 7.28 (d,J=9.2 Hz, 2H), 4.34 (d, J=6.0 Hz, 2H). MS: m/z 403.9 (M+H⁺).

Example 421: Synthesis of1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (s, 1H), 9.09 (s, 1H), 8.11-8.04 (m,1H), 7.78 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.59-7.45 (m, 3H),7.40-7.33 (m, 1H), 6.59 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H). MS:m/z 392.9 (M+H⁺).

Example 422: Synthesis of1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(2,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.26 (s, 1H), 8.29 (s, 1H), 8.12-8.04 (m,1H), 8.09 (d, J=8.0 Hz, 2H), 7.63 (d, J=9.2 Hz, 2H), 7.56-7.49 (m, 1H),7.41-7.33 (m, 1H), 7.01 (s, 1H), 6.89 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6Hz, 2H). MS: m/z 393.9 (M+H⁺).

Example 423: Synthesis of1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 2,4-dichloro-benzenethiol (895.35 mg, 5.0 mmol)in DMF (30 mL) was added 1-fluoro-4-nitro-benzene (1181.63 mg, 7.5 mmol)and K₂CO₃ (2.07 g, 15 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE:EA=50:1) to afford2,4-dichloro-1-(4-nitro-phenylsulfanyl)-benzene (1.85 g, yield 100%) asa white solid.

Step 2: To a solution of 2,4-dichloro-4-(4-nitro-phenylsulfanyl)-benzene(1.85 g, 6.16 mmol) in DCM (30 mL) was added m-CPBA (3188.9 mg, 18.48mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite, the organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE:EA=10:1) to afford2,4-dichloro-4-(4-nitro-benzenesulfonyl)-benzene (1.89 g, 77.5%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ=8.36 (d, J=8.8 Hz, 2H), 8.32 (d,J=8.8 Hz, 1H), 8.12 (d, J=8.8 Hz, 2H), 7.57-7.51 (dd, J=2.0, 2.0 Hz,1H), 7.49 (d, J=1.6 Hz, 1H).

Step 3: To a solution of2,4-dichloro-4-(4-nitro-benzenesulfonyl)-benzene (500 mg, 1.5 mmol) inEtOH (25 mL) and H₂O (5 mL) was added NH₄Cl (401.17 mg, 7.5 mmol), ironpowder (418.8 mg, 7.5 mmol). The reaction mixture was stirred at 80° C.overnight. Iron powder was filtered off and the filtrate wasconcentrated in vacuum to give a residue, which was purified by flash togive 4-(2,4-dichloro-benzenesulfonyl)-phenylamine (370 mg, yield: 81.3%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.14 (d, J=8.8 Hz, 1H),7.81 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 6.61 (d,J=8.0 Hz, 2H), 6.32 (s, 2H).

Step 4: To a solution of 4-(2,4-dichloro-benzenesulfonyl)-phenylamine(370 mg, 1.2 mmol) in DCM (30 mL) was added phenyl chloroformate (375.76mg, 2.4 mmol) and TEA (242.8 mg, 2.4 mmol), the mixture was stirred at0° C. for 1 hr. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=3/1) to afford[4-(2,4-dichloro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(380.0 mg, 73.5%) as a white solid.

Step 5: To a solution of[4-(2,4-dichloro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (80mg, 0.19 mmol) in ACN (30 mL) was added c-pyridin-4-yl-methylamine(41.09 mg, 0.38 mmol) and TEA (38.46 mg, 0.38 mmol), the mixture wasstirred at 80° C. for 3 hrs. The reaction was monitored by LCMS. Aftercompletion, the mixture was concentrated in vacuum to give a residue,the residue was purified by prep-HPLC to give1-[4-(2,4-dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea(40.4 mg, yield: 66.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.39 (s, 1H), 8.49 (d, J=5.6 Hz, 2H), 8.22 (d, J=8.4 Hz, 1H), 7.85 (d,J=2.0 Hz, 1H), 7.78 (d, J=9.2 Hz, 2H), 7.76-7.71 (dd, J=1.6, 2.0 Hz,1H), 7.63 (d, J=8.8 Hz, 2H), 7.27 (d, J=5.6 Hz, 2H), 6.98 (t, J=5.6 Hz,1H), 4.33 (d, J=4.8 Hz, 2H). MS: m/z 435.9 (M+H⁺).

Example 424: Synthesis of1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.66 (s, 1H), 9.10 (s, 1H), 8.21 (d, J=8.4Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 780-7.72 (m, 3H), 7.61 (d, J=8.8 Hz,2H), 7.56-7.37 (m, 2H), 6.60 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.2 Hz, 2H).MS: m/z 424.8 (M+H⁺).

Example 425: Synthesis of1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.29 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=8.8Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.78 (d, J=9.2 Hz, 2H), 7.76-7.71 (dd,J=2.0, 2.0 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.01 (s, 1H), 6.90 (t, J=5.6Hz, 1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z 425.8 (M+H⁺).

Example 426: Synthesis of1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3,5-difluoro-benzenethiol (584.6 mg, 4.0 mmol)in DMF (30 mL) was added 1-fluoro-4-nitro-benzene (846.59 mg, 6.0 mmol)and K₂CO₃ (1.66 g, 12.0 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=50/1) to afford1,3-difluoro-5-(4-nitro-phenylsulfanyl)-benzene (969 mg, yield: 90.6%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=8.16 (d, J=8.8 Hz, 2H),7.36 (d, J=8.8 Hz, 2H), 703-6.95 (m, 1H), 6.89-6.82 (m, 1H).

Step 2: To a solution of 1,3-difluoro-5-(4-nitro-phenylsulfanyl)-benzene(969 mg, 3.63 mmol) in DCM (50 mL) was added m-CPBA (2208.77 mg, 10.88mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite, the organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE:EA=10:1) to afford1,3-difluoro-5-(4-nitro-benzenesulfonyl)-benzene (968 mg, 89.2%) as awhite solid.

Step 3: To a solution of1,3-difluoro-5-(4-nitro-benzenesulfonyl)-benzene (500 mg, 1.67 mmol) inMeOH (30 mL), was added Pd/C (10% wet, 50 mg). The reaction mixture wasstirred at room temperature under H₂ (1 atm) overnight. Pd/C wasfiltered off and the filtrate was concentrated to dryness in vacuum. Theresidue was purified by flash to give4-(3,5-difluoro-benzenesulfonyl)-phenylamine (447 mg, yield: 99.4%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.66-7.55 (m, 5H), 6.63 (d,J=8.8 Hz, 2H), 6.33 (s, 2H).

Step 4: To a solution of 4-(3,5-difluoro-benzenesulfonyl)-phenylamine(447 mg, 1.66 mmol) in DCM (30 mL) was added phenyl chloroformate (519.8mg, 3.32 mmol) and TEA (335.98 mg, 3.32 mmol), the mixture was stirredat 0° C. for 1 hr. The reaction was monitored by TLC. After completion,the mixture was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(380 mg, yield: 58.7%) as a white solid.

Step 5: To a solution of[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (80mg, 0.2 mmol) in ACN (20 mL) was added c-pyridin-4-yl-methylamine (433.2mg, 0.4 mmol) and TEA (40.48 mg, 0.4 mmol), the mixture was stirred at80° C. for 3 hrs. The reaction was monitored by LCMS. After completion,the mixture was concentrated in vacuum to give a residue, which waspurified by prep-HPLC to give1-[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea(56 mg, yield: 62.8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.39 (s, 1H), 8.49 (J=6.4 Hz, 2H), 7.89 (d, J=8.8 Hz, 2H), 7.72-7.60(m, 5H), 7.27 (d, J=6.0 Hz, 2H), 6.99 (t, J=6.0 Hz, 1H), 4.33 (d, J=5.6Hz, 2H). MS: m/z 403.9 (M+H⁺).

Example 427: Synthesis of1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.66 (s, 1H), 9.11 (s, 1H), 7.87 (d, J=8.8Hz, 2H), 7.68 (d, J=6.0 Hz, 2H) 7.65-7.33 (m, 5H), 6.63 (t, J=5.6 Hz,1H), 4.15 (d, J=5.6 Hz, 2H). MS: m/z 392.9 (M+H⁺).

Example 428: Synthesis of1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(3,5-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.29 (s, 1H), 7.89 (d, J=9.2Hz, 2H), 7.71-7.59 (m, 5H), 7.00 (s, 1H), 6.89 (t, J=4.8 Hz, 1H), 4.37(d, J=5.6 Hz, 2H). MS: m/z 393.9 (M+H⁺).

Example 429: Synthesis of1-(3-Cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 2-chloro-5-nitrobenzonitrile (1 g, 5.49 mmol)and 3,5-difluorobenzenethiol (960 mg, 6.6 mmol) in DMF (20 mL) was addedK₂CO₃ (2.3 g, 16 mmol). The reaction was stirred at 80° C. overnight.The residue was poured into H₂O (20 mL) and the aqueous phase wasextracted with EA (30 mL×2). The organic layer was washed with brine (20mL), dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel column (PE/EA=10/1) to give2-((3,5-difluorophenyl)thio)-5-nitrobenzonitrile (620 mg, yield: 39%) asa yellow solid.

Step 2: To a solution of2-((3,5-difluorophenyl)thio)-5-nitrobenzonitrile (620 mg, 2.1 mmol) inDCM (20 mL), was added m-CPBA (815 mg, 4.7 mmol). The reaction wasstirred at room temperature for 2 hrs. The mixture was concentrated andthe residue was purified by silica gel column (PE/EA=5/1) to give2-((3,5-difluorophenyl)sulfonyl)-5-nitrobenzonitrile (750 mg, crude) asa white solid.

Step 3: To a solution of2-((3,5-difluorophenyl)sulfonyl)-5-nitrobenzonitrile (600 mg, 1.85 mmol)in EtOH/H₂O (4/1, 25 mL), was added NH₄Cl (980 mg, 18.5 mmol) and iron(725 mg, 13 mmol). The reaction was stirred at 80° C. for 2.5 hrs. Theresidue was poured into H₂O (20 mL) and the aqueous phase was extractedwith EA (20 mL). The organic layer was washed with brine (20 mL), driedover Na₂SO₄ and concentrated. The residue was purified by silica gelcolumn (PE/EA=1/1) to give5-amino-2-((3,5-difluorophenyl)sulfonyl)benzonitrile (300 mg, yield:55%) as a yellow solid.

Step 4: To a solution of5-amino-2-((3,5-difluorophenyl)sulfonyl)benzonitrile (150 mg, 0.51 mmol)in DCM (20 mL) was added TEA (153 mg, 1.53 mmol). When it was cooled to0° C., to the above solution was added phenyl chloroformate (240 mg,1.53 mmol) slowly. The reaction was stirred at room temperature for 3hrs. The residue was concentrated and the residue was purified by silicagel column (PE/EA=2/1) to give(3-cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)carbamate (80 mg, yield:38%) as a white oil.

Step 5: To a solution of phenyl(3-cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)carbamate (80 mg, 0.19mmol) and pyridin-4-ylmethanamine (25 mg, 0.23 mmol) in ACN (20 mL), wasadded TEA (58 mg, 0.57 mmol). The reaction was stirred at 80° C. for 3hrs. The residue was poured into H₂O (15 mL) and the aqueous phase wasextracted with EA (15 mL). The organic layer was washed with brine (20mL), dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC (NaHCO₃) to give1-(3-cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea(5.3 mg, yield: 6%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47(d, J=6.0 Hz, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 7.86(dd, J=8.8 Hz, 1H), 7.65-7.63 (m, 2H), 7.42 (d, J=6.0 Hz, 3H), 4.46 (s,2H). MS: m/z 429.0 (M+H⁺).

Example 430: Synthesis of1-(2-Cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 5-fluoro-2-nitrobenzonitrile 1 g, 6 mmol) and3,5-difluorobenzenethiol (1.03 g, 7.05 mmol) in DMF (20 mL), was addedK₂CO₃ (2.5 g, 18 mmol). The reaction was stirred at 80° C. for 1.5 hrs.The residue was poured into H₂O (20 mL) and the aqueous phase wasextracted with EA (30 mL×2). The organic layer was washed with brine (25mL), dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel column (PE/EA=3/1) to give5-((3,5-difluorophenyl)thio)-2-nitrobenzonitrile (1.4 g, yield: 90%) asa yellow solid.

Step 2: To a solution of5-((3,5-difluorophenyl)thio)-2-nitrobenzonitrile (1 g, 3.42 mmol) inEtOH/H₂O (4/1, 25 mL), was added NH₄Cl (1.8 g, 34.2 mmol) and iron (1.3g, 24 mmol). The reaction was stirred at 80° C. for 2 hrs. The residuewas poured into H₂O (20 mL) and the aqueous phase was extracted with EA(20 mL). The organic layer was washed with brine (35 mL), dried overNa₂SO₄ and concentrated. The residue was purified by silica gel column(PE/EA=4/1) to give 2-amino-5-((3,5-difluorophenyl)thio)benzonitrile(800 mg, yield: 88%) as a yellow solid.

Step 3: To a solution of2-amino-5-((3,5-difluorophenyl)thio)benzonitrile (800 mg, 3.05 mmol) inDCM (20 mL), was added TEA (920 mg, 9.15 mmol). When it was cooled to 0°C., to the above solution was added phenyl chloroformate (1.4 g, 9.15mmol) slowly. The reaction was stirred at room temperature for 1 hr. Theresidue was concentrated and purified by silica gel column (PE/EA=8/1)to give phenyl (2-cyano-4-((3,5-difluorophenyl)thio)phenyl)carbamate(crude) as a yellow oil.

Step 4: To a solution of phenyl(2-cyano-4-((3,5-difluorophenyl)thio)phenyl)carbamate (crude, 3 mmol)and pyridin-4-ylmethanamine (388 mg, 3.6 mmol) in CAN (20 mL), was addedTEA (909 mg, 9 mmol). The reaction was stirred at 80° C. for 1 hr. Theresidue was poured into H2O (20 mL) and the aqueous phase was extractedwith EA (20 mL). The organic layer was washed with brine (25 mL), driedover Na₂SO₄ and concentrated. The residue was purified by silica gelcolumn (PE/EA=3/1) to give1-(2-cyano-4-((3,5-difluorophenyl)thio)phenyl)-3-(pyridin-4-ylmethyl)urea(500 mg, yield: 42%) as a white solid.

Step 5: To a solution of1-(2-cyano-4-((3,5-difluorophenyl)thio)phenyl)-3-(pyridin-4-ylmethyl)urea(200 mg, 0.5 mmol) in DCM (20 mL), was added m-CPBA (175 mg, 1.0 mmol).The reaction was stirred at room temperature for 3 hrs. The residue wasconcentrated and purified by prep-HPLC (NH₄HCO₃) to give1-(2-cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea(30.9 mg, yield: 14%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=11.38 (s, 1H), 9.52 (s, 1H), 8.80 (s, 1H), 8.44 (d, J=5.6 Hz, 2H),8.10 (d, J=7.2 Hz, 1H), 7.80 (s, 2H), 7.68-7.63 (m, 1H), 7.26-7.23 (m,3H), 5.21 (s, 2H). MS: m/z 429.7 (M+H⁺).

Example 431: Synthesis of1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3,4-dichloro-benzenethiol (537.21 mg, 3.0 mmol)in DMF (20 mL) was added 1-chloro-4-nitro-benzene (708.97 mg, 4.5 mmol)and K₂CO₃ (1.24 g, 9.0 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=30/1) to afford1,2-dichloro-4-(4-nitro-phenylsulfanyl)-benzene (851 mg, yield: 94%) asa yellow solid.

Step 2: To a solution of 1,2-dichloro-4-(4-nitro-phenylsulfanyl)-benzene(851 mg, 2.83 mmol) in DCM (30 mL) was added m-CPBA (1465.03 mg, 8.49mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite. The organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE:EA=10:1) to afford1,2-dichloro-4-(4-nitro-benzenesulfonyl)-benzene (937 mg, 99.4%) as awhite solid. ¹H NMR (400 MHz, CDCl₃): δ=8.38 (d, J=8.8 Hz, 2H), 8.13 (d,J=8.8 Hz, 2H), 8.047 (d, J=2.0 Hz, 1H), 7.81-7.77 (dd, J=1.6, 2.4 Hz,1H), 7.64 (d, J=8.4 Hz, 1H).

Step 3: To a solution of1,2-dichloro-4-(4-nitro-benzenesulfonyl)-benzene (937 mg, 2.82 mmol) inEtOH (15 mL) and H₂O (5 mL) was added NH₄Cl (754.21 mg, 14.1 mmol), ironpowder (787.48 mg, 14.1 mmol). The reaction mixture was stirred at 80°C. overnight. Iron powder was filtered off and the filtrate wasconcentrated in vacuum to give a residue, which was purified by flash togive 4-(3,4-dichloro-benzenesulfonyl)-phenylamine (724.48 mg, yield:85%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.05 (d, J=2.0 Hz,1H), 7.86-7.82 (m, 1H), 7.81-7.76 (dd, J=2.0, 2.0 Hz, 1H), 7.62-7.57(dd, J=1.6, 2.0 Hz, 2H), 6.66-6.60 (dd, J=1.6, 2.0 Hz, 2H), 6.30 (s,2H).

Step 4: To a solution of 4-(3,4-dichloro-benzenesulfonyl)-phenylamine(190 mg, 0.63 mmol) in DCM (30 mL) was added phenyl chloroformate(197.27 mg, 1.26 mmol) and TEA (127.51 mg, 1.26 mmol), the mixture wasstirred at 0° C. for 1 hr. The reaction was monitored by TLC. Aftercompletion, the mixture was concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=3/1) to afford[4-(3,4-dichloro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(240.0 mg, 86.3%) as a white solid.

Step 5: To a solution of[4-(3,4-dichloro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (60mg, 0.14 mmol) in ACN (20 mL) was added c-pyridin-4-yl-methylamine(30.27 mg, 0.28 mmol) and TEA (28.33 mg, 0.28 mmol), the mixture wasstirred at 80° C. for 3 hrs. The reaction was monitored by LCMS. Aftercompletion, the mixture was concentrated in vacuum to give a residue,which was purified by prep-HPLC to give1-[4-(3,4-dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea(40.4 mg, yield: 66.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=9.38 (s, 1H), 8.53-8.46 (dd, J=1.6, 1.2 Hz, 2H), 8.15 (d, J=1.6 Hz,1H), 7.91-7.83 (m, 4H), 7.64 (d, J=9.2 Hz, 2H), 7.27 (d, J=6.0 Hz, 2H),6.98 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 435.8 (M+H⁺).

Example 432: Synthesis of1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (s, 1H), 9.14 (s, 1H), 8.14 (d, J=1.2Hz, 1H), 7.90-7.84 (m, 4H), 7.61 (d, J=9.2 Hz, 2H), 7.54-7.45 (m, 2H),6.62 (t, J=5.6 Hz, 1H), 4.15 (d, J=4.8 Hz, 2H). MS: m/z 424.8 (M+H⁺).

Example 433: Synthesis of1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.22 (s, 1H), 8.28 (s, 1H), 8.14 (d, J=1.2Hz, 1H), 7.89-7.85 (m, 4H), 7.62 (d, J=9.2 Hz, 2H), 7.00 (s, 1H), 6.86(t, J=5.6 Hz, 1H), 4.37 (d, J=5.2 Hz, 2H). MS: m/z 425.8 (M+H⁺).

Example 434: Synthesis of1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3,4-difluoro-benzenethiol (584.6 mg, 4.0 mmol)in DMF (30 mL) was added 1-fluoro-4-nitro-benzene (846.59 mg, 6.0 mmol)and K₂CO₃ (1.66 g, 12.0 mmol), the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum to give a residue, which was purifiedby a silica gel column (PE/EA=50/1) to afford1,2-difluoro-4-(4-nitro-phenylsulfanyl)-benzene (778 mg, yield: 77.6%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.15 (d, J=9.2 Hz, 2H),7.84-7.77 (m, 1H), 7.68-7.59 (m, 1H), 7.51-7.44 (m, 1H), 7.35 (d, J=8.8Hz, 2H).

Step 2: To a solution of 1,2-difluoro-4-(4-nitro-phenylsulfanyl)-benzene(778 mg, 2.91 mmol) in DCM (30 mL) was added m-CPBA (1772.29 mg, 8.73mmol), the mixture was stirred at room temperature overnight. Thereaction was monitored by TLC. After completion, the mixture wasquenched with saturated aqueous sodium sulfite, the organic layer wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE:EA=10:1) to afford1,2-difluoro-4-(4-nitro-benzenesulfonyl)-benzene (840 mg, 96.4%) as awhite solid.

Step 3: To a solution of1,2-difluoro-4-(4-nitro-benzenesulfonyl)-benzene (300 mg, 1.0 mmol) inMeOH (30 mL), was added Pd/C (10% wet, 30 mg). The reaction mixture wasstirred at room temperature under H₂ (1 atm) overnight. Pd/C wasfiltered off and the filtrate was concentrated to dryness in vacuum. Theresidue was purified by flash to give4-(3,4-difluoro-benzenesulfonyl)-phenylamine (209 mg, yield: 77.5%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.00-7.92 (m, 1H), 7.75-7.69(m, 1H), 7.68-7.62 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz,2H), 6.27 (s, 2H).

Step 4: To a solution of 4-(3,4-difluoro-benzenesulfonyl)-phenylamine(209 mg, 0.78 mmol) in DCM (40 mL) was added phenyl chloroformate (244.2mg, 1.56 mmol) and TEA (157.86 mg, 1.56 mmol), the mixture was stirredat 0° C. for 1 hr. The reaction was monitored by TLC. After completion,the mixture was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(329 mg, yield:>1) as a white solid.

Step 5: To a solution of[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester (50mg, 0.13 mmol) in ACN (30 mL) was added c-pyridin-4-yl-methylamine(28.12 mg, 0.26 mmol) and TEA (28.31 mg, 0.26 mmol), the mixture wasstirred at 80° C. for 3 hrs. The reaction was monitored by LCMS. Aftercompletion, the mixture was concentrated in vacuum to give a residue,the residue was purified by prep-HPLC to give1-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea(8.2 mg, yield: 15.8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ=9.36 (s, 1H), 8.49 (J=6.0 Hz, 2H), 8.10-8.03 (m, 1H), 7.85 (d, J=8.8Hz, 2H), 7.83-7.77 (m, 1H), 7.73-7.66 (m, 1H), 7.63 (d, J=8.8 Hz, 2H),7.27 (d, J=6.0 Hz, 2H), 6.97 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H).MS: m/z 403.9 (M+H⁺).

Example 435: Synthesis of1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 9.04 (s, 1H), 8.09-8.02 (m,1H), 7.84 (d, J=9.2 Hz, 2H), 7.82-7.76 (m, 1H), 7.72-7.64 (m, 1H), 7.60(d, J=8.8 Hz, 2H), 7.56-7.45 (m, 2H), 6.57 (t, J=5.6 Hz, 1H), 4.14 (d,J=5.2 Hz, 2H). MS: m/z 392.9 (M+H⁺).

Example 436: Synthesis of1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(3,4-difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d6): δ=9.21 (s, 1H), 8.28 (s, 1H), 8.10-8.03 (m,1H), 7.85 (d, J=8.4 Hz, 2H), 7.83-7.77 (m, 1H), 7.73-7.66 (m, 1H), 7.61(d, J=9.2 Hz, 2H), 7.00 (s, 1H), 6.86 (t, J=6.0 Hz, 1H), 4.37 (d, J=5.6Hz, 2H). MS: m/z 393.9 (M+H⁺).

Example 437: Synthesis ofPyridin-4-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea

The title compound was prepare using genera procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.49-8.48 (m, 2H), 8.00 (s, 2H), 7.94 (d, J=9.2Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.40 (d, J=6.0 Hz, 2H), 4.47 (s, 2H).MS: m/z 374.9 (M+H⁺).

Example 438: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea

Step 1: A solution of 4-nitro-benzenethiol (3.0 g, 19 mmol),2-bromo-thiazole (3.79 g, 23 mmol), K₂CO₃ (7.8 g, 57 mmol) and CuI (0.36g, 1.9 mmol) in DMF (10 mL) was stirred at 140° C. overnight. Thereaction solution was partitioned between EA (50 mL) and water (100 mL).The organic layer was washed with water (60 mL) and brine (60 mL), driedover Na₂SO₄ and concentrated in vacuum. The residue was purified bysilica gel column (PE/EA=30/1) to give2-(4-nitro-phenylsulfanyl)-thiazole (2.21 g, yield: 48%) as yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ=9.48 (s, 1H), 8.29-8.16 (m, 3H),7.36 (d, J=9.0 Hz, 2H). MS: m/z 239.0 (M+H⁺).

Step 2: To a mixture of 2-(4-nitro-phenylsulfanyl)-thiazole (2.21 g, 9.0mmol) in DCM (20 mL) was added m-CPBA (7.74 g, 45 mmol) at 0° C. slowly.Then the mixture was stirred at room temperature overnight. To themixture was added Na₂SO₃, filtered and washed with NaHCO₃ andconcentrated. The residue was purified with chromatography (PE/EA=3/1)to give 2-(4-nitro-benzenesulfonyl)-thiazole (1.8 g, yield: 74%) as awhite solid. MS: m/z 271.0 (M+H⁺).

Step 3: A mixture of 2-(4-nitro-benzenesulfonyl)-thiazole (1.5 g, 5.0mmol), Fe (0.9 g, 15 mmol) and NH₄Cl (0.8 g, 15 mmol) in EtOH/H₂O (10mL/3 mL) was stirred at 90° C. overnight. The reaction solution wasfiltered. The filtrate was concentrated to give4-(thiazole-2-sulfonyl)-phenylamine (1 g, yield: 76%) as a white solid.MS: m/z 241.0 (M+H⁺).

Step 4: To a solution of 4-(Thiazole-2-sulfonyl)-phenylamine (100 mg,0.40 mmol) in DCM (20 mL) was added pyridine (66 mg, 0.80 mmol) andphenyl chloroformate (187 mg, 1.20 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 2 hrs. The reaction was completeddetected by LC-MS. The reaction was quenched with water (10 mL),extracted with DCM (10 mL×3) and concentrated to give[4-(thiazole-2-sulfonyl)-phenyl]-carbamic acid phenyl ester (150 mg,yield: 79%) as a white solid. MS: m/z 361.0 (M+H⁺).

Step 5: To a solution of [4-(Thiazole-2-sulfonyl)-phenyl]-carbamic acidphenyl ester (50 mg, 0.13 mmol) in ACN (10 mL) was added TEA (39 mg,0.39 mmol) and C-(1H-pyrazol-4-yl)-methylamine (24 mg, 0.28 mmol). Thereaction mixture was stirred at 80° C. for 3 hrs. The reaction wasconcentrated and purified by prep-HPLC to give1-(1H-pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea (5 mg,yield: 10%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=7.98 (s, 2H),7.92-7.90 (m, 4H), 7.64 (d, J=9.2 Hz, 2H), 4.32 (s, 2H). MS: m/z 363.9(M+H⁺).

Example 439: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea. ¹HNMR (400 MHz, CD₃OD): δ=8.17 (s, 1H), 8.04 (s, 2H), 7.94 (d, J=9.2 Hz,2H), 7.67 (d, J=9.2 Hz, 2H), 7.06 (s, 1H), 4.50 (s, 2H). MS: m/z 364.9(M+H⁺).

Example 440: Synthesis of1-Pyridin-4-ylmethyl)-3-(4-(thiazol-5-ylsulfonyl)phenyl)urea

Step 1: To a solution of 4-Nitro-benzenethiol (50.0 mg, 0.32 mmol) inDMF (5 mL) was added 5-Bromo-thiazole (63.4 mg, 0.39 mmol), K₂CO₃ (132.7mg, 0.96 mmol) and CuI (6.1 mg, 0.03 mmol). The reaction mixture wasstirred at 140° C. under N₂ overnight. The reaction was completeddetected by LC-MS. The reaction was quenched with water (5 mL) andextracted with DCM (10 mL×3). The combined organic layer was washed withbrine (10 mL) and water (10 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silia gel chromatography (PEto PE/EA=20/1) to give 2-(4-Nitro-phenylsulfanyl)-thiazole (60.0 mg,yield: 78%) as a yellow solid. MS: m/z 239.0 (M+H⁺).

Step 2: To a solution of 2-(4-Nitro-phenylsulfanyl)-thiazole (405.0 mg,1.70 mmol) in DCM (30 mL) was added m-CPBA (1.73 g, 8.50 mmol, 85% Wt)at 0° C. The reaction mixture was allowed to warm to room temperatureovernight. The reaction was completed detected by LC-MS. The reactionwas quenched with Na₂SO₃ aqueous (10 mL) and extracted with DCM (20mL×3). The combined organic layer was washed with NaHCO₃ aqueous (20 mL)and water (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silia gel chromatography (PE to PE/EA=20/1) togive 2-(4-Nitro-benzenesulfonyl)-thiazole (322.0 mg, yield: 70%) as awhite solid. MS: m/z 271.0 (M+H⁺).

Step 3: To a solution of 2-(4-Nitro-benzenesulfonyl)-thiazole (2.60 g,9.6 mmol) in EtOH/H₂O (50/10 mL) was added Iron powder (2.68 g, 48.0mmol) and NH₄Cl (2.57 g, 48.0 mmol) at room temperature. The reactionmixture was heated to 80° C. overnight. The reaction was completeddetected by LC-MS. The reaction mixture was concentrated and thenextracted with DCM (30 mL×3). The combined organic layer was washed withdilute HCl (1 mol/L, 30 mL) and water (30 mL), dried over Na₂SO₄,filtered and concentrated to give 4-(Thiazole-2-sulfonyl)-phenylamine(1.62 g, yield: 70%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ=8.14 (d, J=3.2 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.8 Hz,2H), 6.67 (d, J=8.8 Hz, 2H), 6.08 (br s, 2H).

Step 4: To a solution of 4-(Thiazole-2-sulfonyl)-phenylamine (200.0 mg,0.83 mmol) in DCM (20 mL) was added pyridine (197.0 mg, 2.49 mmol) andphenyl chloroformate (260.0 mg, 1.66 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 1 hr. The reaction was completeddetected by LC-MS. The reaction was quenched with water (5 mL) andextracted with DCM (20 mL×3). The combined organic layer was washed withbrine (20 mL) and water (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by re-crystallization from etherabsolute (10 mL) to give [4-(Thiazole-2-sulfonyl)-phenyl]-carbamic acidphenyl ester (264.0 g, yield: 88%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆): δ=10.88 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.10 (d, J=3.0 Hz,1H), 7.99 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.50-7.23 (m, 5H).

Step 5: To a solution of [4-(Thiazole-2-sulfonyl)-phenyl]-carbamic acidphenyl ester (80.0 mg, 0.22 mmol) in ACN (20 mL) was added TEA (111.3mg, 1.1 mmol) and C-Pyridin-4-yl-methylamine (47.6 mg, 0.44 mmol). Thereaction mixture was stirred at 80° C. for 2 hrs. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (5 mL)and extracted with DCM (20 mL×3). The combined organic layer was washedwith brine (20 mL) and water (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by prep.HPLC to give1-Pyridin-4-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea (17.0 mg,yield: 21%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.47 (s, 1H),8.50 (d, J=5.6 Hz, 2H), 8.22 (d, J=3.2 Hz, 1H), 8.08 (d, J=3.2 Hz, 1H),7.87 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.28 (d, J=6.0 Hz, 2H),7.02 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H). MS: m/z 374.9 (M+H⁺).

Example 441: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl)-3-(4-(thiazol-5-ylsulfonyl)phenyl)urea. ¹H NMR(400 MHz, DMSO-d₆): δ=9.26 (s, 1H), 8.21 (d, J=3.2 Hz, 1H), 8.08 (d,J=2.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.66 (d, J=9.2 Hz, 2H), 7.53 (s,2H), 6.74 (t, J=5.4 Hz, 1H), 4.15 (d, J=5.6 Hz, 2H). MS: m/z 364.1(M+H⁺).

Example 442: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-pyridin-4-ylmethyl)-3-(4-(thiazol-5-ylsulfonyl)phenyl)urea. ¹H NMR(400 MHz, CD₃OD): δ=8.14 (s, 1H), 7.98 (s, 2H), 7.92 (d, J=8.8 Hz, 2H),7.64 (d, J=8.8 Hz, 2H), 7.04 (s, 1H), 4.47 (s, 2H). MS: m/z 364.9(M+H⁺).

Example 443: Synthesis of1-(4-((1H-Pyrazol-4-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, CD₃OD): δ=8.75 (d, J=6.0 Hz, 2H), 8.04-7.98 (m, 4H),7.85 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 4.67 (s, 2H). MS: m/z358.0 (M+H⁺).

Example 444: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)urea

Step 1: To a solution of 4-Benzylsulfanyl-1-isopropyl-1H-pyrazole (1 g,5.2 mmol) in toluene (10 mL) was added AlCl₃ (1.0 5 g, 7.8 mmol). Thereaction was stirred at room temperature for 5 hrs. Then the reactionmixture was concentrated. The residue was purified by silica gel columnchromatography (PE/EA=3/1) to give 1H-pyrazole-4-thiol (420 mg, yield:81%) as red oil.

Step 2: To a solution of 1H-pyrazole-4-thiol (420 mg, 4.2 mmol) in DCM(5 mL) was added DHP (352 mg, 4.2 mmol) and TsOH (144 mg, 0.84 mmol).The reaction was stirred at room temperature for 3 hrs. The reactionmixture was concentrated and the residue was purified by silica gelcolumn chromatography (PE/EA=3/1) to give1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (220 mg, yield: 29%) asyellow oil.

Step 3: To a solution of1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (220 mg, 1.19 mmol) inDMF (5 mL) was added Cs₂CO₃ (1.16 g, 3.57 mmol) and1-Fluoro-4-nitro-benzene (252 mg, 1.79 mmol). The reaction was stirredat 80° C. for 3 hrs. Then the reaction was extracted with EA (10 mL×2).The combined organic layer was washed with brine (10 mL×2), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (PE/EA=3/1) to give4-((4-nitrophenyl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (290mg, yield: 80%) as yellow oil.

Step 4: To a mixture of4-((4-nitrophenyl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (270mg, 0.885 mmol) in THF (5 mL) and H₂O (5 mL) was added oxone (1.08 g,1.77 mmol). The resulting mixture was stirred at room temperature for 3hrs. Then the reaction mixture was filtered and the filtrate wasconcentrated to give4-((4-nitrophenyl)sulfonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(270 mg, yield: 91%) as yellow oil. MS: m/z 338.3 (M+H⁺).

Step 5: To a mixture of4-((4-nitrophenyl)sulfonyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(270 mg, 0.801 mmol) in MeOH (10 mL) was added Pd/C (27 mg, 12.2 mmol).The resulting mixture was stirred at room temperature for 3 hrs. Thenthe reaction mixture was filtered and the filtrate was concentrated togive 4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)aniline(200 mg, yield:82%) as colorless oil.

Step 6: To a mixture of4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)aniline (200mg, 0.65 mmol) in DCM (10 mL) was added phenyl chloroformate (203 mg,1.3 mmol) and TEA (262 mg, 2.6 mmol). The resulting mixture was stirredat room temperature for 3 hrs. Then the reaction was extracted with DCM.The combined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give phenyl(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)carbamate(120 mg, yield: 43%) as colorless oil.

Step 7: To a mixture of phenyl(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)carbamate(60 mg, 0.14 mmol) in ACN (10 mL) was addedC-(1H-Pyrazol-4-yl)-methylamine (16 mg, 0.168 mmol) and TEA (42 mg, 0.42mmol). The resulting mixture was stirred at 80° C. for 3 hrs. Then thereaction mixture was concentrated. The residue was extracted with EA.The combined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give1-((1H-pyrazol-4-yl)methyl)-3-(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)urea(70 mg, crude, yield: 100%) as yellow oil.

Step 8: A solution of1-((1H-pyrazol-4-yl)methyl)-3-(4-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phenyl)urea(70 mg, crude, 0.14 mmol) in a solution of HCl in MeOH (4M, 5 mL) wasstirred at room temperature for 3 hrs. Then the reaction mixture wasconcentrated and the residue was purified by HPLC to give1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea(12 mg, yield: 8%) as a white solid ¹H NMR (400 MHz, CD₃OD): δ=8.05 (s,2H), 7.86 (d, J=7.2 Hz, 2H), 7.70 (s, 2H), 7.61 (d, J=7.2 Hz, 2H), 4.31(s, 2H). MS: m/z 347.0 (M+H⁺).

Example 445: Synthesis of1-(4-((1H-Pyrazol-4-yl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, CD₃OD): δ=8.14 (s, 1H), 8.04 (s, 2H), 7.84 (d, J=7.0Hz, 2H), 7.54 (d, J=7.2 Hz, 2H), 7.03 (s, 1H), 4.46 (s, 2H). MS: m/z347.9 (M+H⁺).

Example 446: Synthesis of1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of NaH (0.63 g, 15.76 mmol, 60%) in THF (20 mL)was added dropwise a solution of 4-Benzylsulfanyl-1H-pyrazole (3.0 g,15.76 mmol) in THF (20 mL) at 0° C. The reaction mixture was stirred at0° C. for 2 hrs. To the reaction mixture was added dropwise CH₃I (1.96mL, 31.52 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for another 2 hrs. The reaction was completed detected byLC-MS. The reaction was quenched with water (5 mL) and extracted withDCM (20 mL×3). The combined organic layer was washed with brine (20 mL)and water (20 mL) and concentrated under reduced pressure to give4-Benzylsulfanyl-1-methyl-1H-pyrazole (3.60 g, yield: 100%) as yellowoil. ¹H NMR (400 MHz, DMSO-d₆): δ=7.63 (s, 1H), 7.30-7.18 (m, 6H), 3.86(s, 2H), 3.76 (s, 3H).

Step 2: To a solution of 4-Benzylsulfanyl-1-methyl-1H-pyrazole (3.6 g,17.6 mmol) in toluene (20 mL) was added AlCl₃ (3.5 g, 26.4 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hrs. Thereaction was completed detected by TLC (PE/EA=4/1). The reaction mixturewas used to the next step without further purification.

Step 3: To a solution of Step 2 was added DMSO (20 mL), Cs₂CO₃ (28.7 g,88.1 mmol) and 1-Fluoro-4-nitro-benzene (3.7 g, 26.4 mmol). The reactionmixture was stirred at 80° C. under N₂ for 10 hrs. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (20mL) and extracted with DCM (30 mL×3). The combined organic layer waswashed with brine (30 mL) and water (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by silia gel chromatography(PE to PE/EA=5/1) to give1-Methyl-4-(4-nitro-phenylsulfanyl)-1H-pyrazole (2.05 g, yield: 50%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.17 (s, 1H), 8.12 (d,J=9.2 Hz, 2H), 7.70 (s, 1H), 7.25 (d, J=8.8 Hz, 2H), 3.39 (s, 3H).

Step 4: To a solution of 1-Methyl-4-(4-nitro-phenylsulfanyl)-1H-pyrazole(1.00 g, 4.25 mmol) in DCM (20 mL) was added m-CPBA (2.20 g, 12.75 mmol,85% Wt) at 0° C. The reaction mixture was allowed to warm to roomtemperature for 1 hr. The reaction was completed detected by LC-MS. Thereaction was quenched with Na₂SO₃ aqueous (10 mL) and extracted with DCM(20 mL×3). The combined organic layer was washed with NaHCO₃ aqueous (20mL) and water (20 mL) and concentrated. The residue was purified bysilia gel chromatography (PE to PE/EA=10/1) to give1-Methyl-4-(4-nitro-benzenesulfonyl)-1H-pyrazole (1.05 g, yield: 93%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.59 (s, 1H), 8.41 (d, J=8.8Hz, 2H), 8.19 (d, J=8.8 Hz, 2H), 8.04 (s, 1H), 3.88 (s, 3H).

Step 5: To a solution of1-Methyl-4-(4-nitro-benzenesulfonyl)-1H-pyrazole (1.00 g, 3.74 mmol) inEtOH/H₂O (30 mL/10 mL) was added iron powder (1.04 g, 18.71 mmol) andNH₄Cl (1.00 g, 18.71 mmol) at room temperature. The reaction mixture washeated to 80° C. overnight. The reaction was completed detected byLC-MS. The reaction mixture was concentrated and then extracted with DCM(30 mL×3). The combined organic layer was washed with dilute HCl (1mol/L, 30 mL) and water (30 mL) and concentrated under pressure to give4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenylamine (0.79 g, yield: 89%) asa yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ=8.27 (s, 1H), 7.76 (s, 1H),7.51 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 6.11 (br s, 2H), 3.82(s, 3H).

Step 6: To a solution of 4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenylamine(750 mg, 3.16 mmol) in DCM (30 mL) was added pyridine (750 mg, 9.48mmol) and phenyl chloroformate (742 mg, 4.74 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 hrs. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (5 mL)and extracted with DCM (20 mL×3). The combined organic layer was washedwith brine (20 mL) and water (20 mL) and concentrated. The residue waspurified by silia gel chromatography (PE to PE/EA=5/1) to give[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-carbamic acid phenyl ester(890 mg, yield: 79%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=10.73 (s, 1H), 8.41 (s, 1H), 7.90-7.88 (m, 3H), 7.70 (d, J=8.8 Hz,2H), 7.44 (t, J=7.8 Hz, 2H), 7.30-7.23 (m, 3H), 3.86 (s, 3H).

Step 7: To a solution of[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-carbamic acid phenyl ester(90.0 mg, 0.25 mmol) in ACN (5 mL) was added TEA (76 mg, 0.75 mmol) andC-Pyridin-4-yl-methylamine (81 mg, 0.75 mmol). The reaction mixture wasstirred at 80° C. for 2 hrs. The reaction was completed detected byLC-MS. The reaction was quenched with water (5 mL) and extracted withDCM (20 mL×3). The combined organic layer was washed with brine (20 mL)and water (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by prep.HPLC to give1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea(65 mg, yield: 70%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.36(s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.38 (s, 1H), 7.85 (s, 1H), 7.76 (d,J=8.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.30 (d, J=6.0 Hz, 2H), 7.00 (t,J=6.2 Hz, 1H), 4.34 (d, J=6.4 Hz, 2H), 3.85 (s, 3H). MS: m/z 372.0(M+H⁺).

Example 447: Synthesis of1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepare using genera procedure of1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.16 (s, 1H), 8.38 (s, 1H), 7.85 (s, 1H),7.75 (d, J=8.8 Hz, 2H), 7.59-7.56 (m, 4H), 6.65 (s, 1H), 4.15 (d, J=4.0Hz, 2H), 3.85 (s, 3H). MS: m/z 361.0 (M+H⁺).

Example 448: Synthesis of1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.63 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H),7.85 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.12 (t,J=5.4 Hz, 1H), 7.01 (s, 1H), 4.37 (d, J=5.6 Hz, 2H), 3.82 (s, 3H). MS:m/z 361.9 (M+H⁺).

Example 449: Synthesis of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=6.0 Hz, 2H), 8.24 (s, 1H),7.84-7.80 (m, 3H), 7.60 (d, J=8.8 Hz, 2H), 7.40 (d, J=6.0 Hz, 2H), 4.57(m, 1H), 4.45 (s, 2H), 1.47 (s, 6H). MS: m/z 400.0 (M+H⁺).

Example 450: Synthesis of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a solution of NaH (460 mg, 11.5 mmol) in THF (20 mL) wasadded 4-Benzylsulfanyl-1H-pyrazole (2 g, 10.5 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1 h. Then 2-Iodo-propane (2.67g, 15.75 mmol) was added to the mixture. The reaction was stirred atroom temperature for 3 hrs. Then the reaction mixture was quenched withNH₄Cl(aq) and extracted with EA (30 ml×2). The combined organic layerwas washed with brine (30 ml×2), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE/EA=5/1) to give4-Benzylsulfanyl-1-isopropyl-1H-pyrazole (2.4 g, yield: 98%) ascolorless oil. MS: m/z 232.9 (M+H⁺).

Step 2: To a solution of 4-Benzylsulfanyl-1-isopropyl-1H-pyrazole (2.4g, 10.3 mmol) in toluene (20 mL) was added AlCl₃ (2 g, 15.5 mmol). Thereaction was stirred at room temperature for 5 hrs. Then DMSO (20 mL),Cs₂CO₃ (16.7 g, 51.5 mmol) and 1-Fluoro-4-nitro-benzene (2.18 g, 15.5mmol) were added to the mixture and the reaction was stirred at 80° C.overnight. Then the reaction was extracted with EA (30 ml×2). Thecombined organic layer was washed with brine (30 mL×2), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (PE/EA=5/1) to give1-Isopropyl-4-(4-nitro-phenylsulfanyl)-1H-pyrazole (760 mg, yield: 26%)as colorless oil. MS: m/z 264.0 (M+H⁺).

Step 3: To a mixture of1-Isopropyl-4-(4-nitro-phenylsulfanyl)-1H-pyrazole (700 mg, 2.66 mmol)in DCM (20 mL) was added m-CPBA (2.2 g, 7.98 mmol). The resultingmixture was stirred at room temperature for 3 hrs. Then the reactionmixture was washed with Na₂SO₃ (aq), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE/EA=10/1) to give1-Isopropyl-4-(4-nitro-benzenesulfonyl)-1H-pyrazole (780 mg, yield: 98%)as a yellow solid. MS: m/z 296.0 (M+H⁺).

Step 4: To a mixture of1-Isopropyl-4-(4-nitro-benzenesulfonyl)-1H-pyrazole (720 mg, 2.44 mmol)in EtOH (10 mL) and H₂O (2 mL) was added Fe (683 mg, 12.2 mmol) andNH₄Cl (646 mg, 12.2 mmol). The resulting mixture was stirred at 80° C.for 3 hrs. Then the reaction mixture was filtered and the filtrate wasconcentrated to give 4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenylamine(560 mg, yield: 86%) as colorless oil. MS: m/z 266.0 (M+H⁺).

Step 5: To a mixture of4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenylamine (540 mg, 2.03 mmol)in DCM (10 mL) was added phenyl chloroformate (475 mg, 5.7 mmol) and TEA(615 mg, 6.09 mmol). The resulting mixture was stirred at roomtemperature for 3 hrs. Then the reaction was extracted with DCM. Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography (PE/EA=1/1) to give[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-carbamic acid phenylester (690 mg, yield: 85%) as a yellow solid. MS: m/z 386.1 (M+H⁺).

Step 6: To a mixture of[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-carbamic acid phenylester (100 mg, 0.259 mmol) in CAN (10 mL) was addedC-(1H-Pyrazol-4-yl)-methylamine (75.5 mg, 0.779 mmol) and TEA (78.6 mg,0.779 mmol). The resulting mixture was stirred at 80° C. for 3 hrs. Thenthe reaction mixture was concentrated. The residue was extracted withEA. The combined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by HPLC to give1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(10 mg, yield: 9%) as a white solid ¹H NMR (400 MHz, CD₃OD): δ=8.23 (s,1H), 7.83-7.80 (m, 3H), 7.70 (s, 2H), 7.58 (d, J=8.8 Hz, 2H), 4.57 (m,1H), 4.29 (s, 2H), 1.50 (s, 6H). MS: m/z 389.0 (M+H⁺).

Example 451: Synthesis of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.24 (s, 1H), 8.14 (s, 1H), 7.84-7.80 (m,3H), 7.59 (d, J=8.8 Hz, 2H), 7.02 (s, 1H), 4.57 (m, 1H), 4.46 (s, 2H),1.47 (s, 6H). MS: m/z 390.0 (M+H⁺).

Example 452: Synthesis of1-(4-(Pyridin-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.38 (brs, 1H), 8.68 (dd, J=8.0, 0.8 Hz,1H), 8.50 (dd, J=4.4, 0.8 Hz, 1H), 8.19-8.08 (m, 2H), 7.82 (d, J=9.2 Hz,2H), 7.70-7.59 (m, 3H), 7.29 (d, J=5.6 Hz, 2H), 6.99 (t, J=6.4 Hz, 1H),4.34 (d, J=6.0 Hz, 2H). MS: m/z 369.0 (M+H⁺).

Example 453: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(Pyridin-2-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 9.17 (s, 1H), 8.71-8.65(m, 1H), 8.17-8.08 (m, 2H), 8.83-7.77 (m, 2H), 7.68-7.63 (m, 1H),7.62-7.59 (m, 2H), 7.58-7.45 (m, 2H), 6.65 (t, J=5.6 Hz, 1H), 4.15 (d,J=5.6 Hz, 2H). MS: m/z 357.9 (M+H⁺).

Example 454: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-(Pyridin-2-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (brs, 1H), 8.70-8.66 (m, 1H), 8.29 (s,1H), 8.17-8.09 (m, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.69-7.59 (m, 3H), 7.01(s, 1H), 6.89 (t, J=5.6 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z 358.9(M+H⁺).

Example 455: Synthesis of1-[4-(Pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea. ¹H NMR (400MHz, CD₃OD): δ=9.06 (d, J=0.8 Hz, 1H), 8.75 (d, J=4.0 Hz, 1H), 8.46 (d,J=4.4 Hz, 2H), 8.33-8.31 (m, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.64 (d, J=9.2Hz, 2H), 7.61-7.58 (m, 1H), 7.38 (d, J=5.6 Hz, 2H), 4.45 (s, 2H). MS:m/z 368.9 (M+H⁺).

Example 456: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(Pyridine-3-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea. ¹H NMR (400MHz, CD₃OD): δ=9.33 (s, 1H), 8.95 (d, J=4.8 Hz, 1H), 8.80 (d, J=8.0 Hz,1H), 8.25 (s, 2H), 8.10-7.98 (m, 1H), 7.94 (d, J=9.2 Hz, 2H), 7.69 (d,J=8.8 Hz, 2H), 4.37 (s, 2H). MS: m/z 358.0 (M+H⁺).

Example 457: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea

Step 1: To a solution of 3-bromo-pyridine (5.0 g, 32 mmol) andphenyl-methanethiol (4.37 g, 35 mmol) in toluene (50 mL) was addedXantphos (1.73 g, 3.0 mmol), Pd₂dba₃ (1.57 g, 1.50 mmol) and DIEA (7.80g, 6 mmol). The reaction was stirred at 110° C. overnight. The resultingwas filtered. The filtrate was concentrated and purified by silica gelcolumn (PE/EA=10/1) to give 3-benzylsulfanyl-pyridine (5.8 g, 96%) as ayellow solid. MS: m/z 201.9 (M+H⁺).

Step 2: To a mixture of 3-benzylsulfanyl-pyridine (1.0 g, 4.9 mmol) intoluene (5 mL) was added AlCl₃ (0.98 g, 7.4 mmol) at 0° C. The reactionwas then stirred for 1 hrs, left the temperature slowly warmed to roomtemperature. The reaction mixture was diluted with DMSO (20 mL),1-fluoro-4-nitro-benzene (1.9 g, 14 mmol) and CsCO₃ (29 g, 90 mmol) wasadded. The resulting mixture was then heated at 60° C. for 4 hrs. Themixture was filtered and the filtrate was diluted with water (40 mL),extracted with EA (30 mL×3) and concentrated. The residue was purifiedby silica gel column (PE/EA=5/1) to give3-(4-nitro-phenylsulfanyl)-pyridine (0.40 g, 20%) as a yellow solid. ¹HNMR (300 MHz, DMSO-d₆): δ=8.74-8.71 (m, 2H), 8.17-8.14 (m, 2H),8.04-8.02 (m, 1H), 7.59-7.54 (m, 1H), 7.36-7.32 (m, 2H). MS: m/z 232.8(M+H⁺).

Step 3: To a mixture of 3-(4-nitro-phenylsulfanyl)-pyridine (0.40 g, 2.0mmol) in DCM (20 mL) was added m-CPBA (5.16 g, 30 mmol) at 0° C. slowly.Then the mixture was stirred at room temperature overnight. To themixture was added Na₂SO₃ and filtered and washed with NaHCO₃, dried overNa₂SO₄, filtered and concentrated. The residue was purified withchromatography (PE/EA=2/1) to give 3-(4-nitro-benzenesulfonyl)-pyridine(222 mg, yield: 42%) as a white solid. MS: m/z 265.0 (M+H⁺).

Step 4: A mixture of 3-(4-nitro-benzenesulfonyl)-pyridine (200 mg, 0.75mmol), Fe (127 mg, 2.27 mmol) and NH₄Cl (121 mg, 2.27 mmol) in EtOH/H₂O(5 mL/2 mL) was stirred at 80° C. overnight. The reaction solution wasfiltered. The filtrate was concentrated to give4-(pyridine-3-sulfonyl)-phenylamine (160 mg, yield: 91%) as a whitesolid. MS: m/z 235.0 (M+H⁺).

Step 5: To a solution of 4-(pyridine-3-sulfonyl)-phenylamine (170 mg,0.73 mmol) in DCM (20 mL) was added pyridine (116 mg, 1.45 mmol) andphenyl chloroformate (227 mg, 1.45 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 2 hrs. The reaction was completeddetected by LC-MS. The reaction was quenched with water (10 mL) andextracted with DCM (10 mL×3). The combined organic layer was dried overNa₂SO₄, filtered and concentrated.

The residue was purified by silica gel column (PE/EA=2/1) to give[4-(pyridine-3-sulfonyl)-phenyl]-carbamic acid phenyl ester (170 mg,yield: 79%) as a white solid. MS: m/z 355.0 (M+H⁺).

Step 6: To a solution of [4-(pyridine-3-sulfonyl)-phenyl]-carbamic acidphenyl ester (50 mg, 0.14 mmol) in ACN (5 mL), was added TEA (60.6 mg,0.6 mmol) and C-Oxazol-5-yl-methylamine (37.9 mg, 0.28 mmol). Thereaction mixture was stirred at 80° C. overnight. The reaction wasquenched with water (10 mL) and extracted with DCM (10 mL×3). Thecombined organic layer was dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column (DCM/MEOH=10/1) andprep-HPLC to give1-oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea (8.2 mg,yield: 16%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=9.06 (d, J=2.0Hz, 1H), 7.46 (dd, J=3.9 Hz, 1.6 Hz, 1H), 8.34-8.31 (m, 1H), 8.14 (s,1H), 7.89 (d, J=8.8 Hz, 2H), 7.64-7.58 (m, 3H), 7.02 (s, 1H), 4.46 (s,2H). MS: m/z 359.0 (M+H⁺).

Example 458: Synthesis of1-(Pyridin-4-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.55 (brs, 1H), 8.85 (d, J=6.0 Hz, 2H),8.50 (d, J=5.6 Hz, 2H), 7.94-7.80 (m, 4H), 7.66 (d, J=8.8 Hz, 2H), 7.29(d, J=5.6 Hz, 2H), 7.09 (t, J=6.0 Hz, 1H), 4.34 (d, J=5.6 Hz, 2H). MS:m/z 368.9 (M+H⁺).

Example 459: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (brs, 1H), 9.16 (s, 1H), 8.85 (dd,J=4.8, 1.6 Hz, 2H), 7.90-7.80 (m, 4H), 7.64 (d, J=9.2 Hz, 2H), 7.60-7.42(m, 2H), 6.61 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 357.9(M+H⁺).

Example 460: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.42 (brs, 1H), 8.85 (dd, J=4.8, 1.6 Hz,2H), 8.28 (s, 1H), 7.90-7.81 (m, 4H), 7.65 (d, J=9.2 Hz, 2H), 7.01 (s,1H), 6.98 (t, J=6.0 Hz, 1H), 4.37 (d, J=5.6 Hz, 2H). MS: m/z 358.9(M+H⁺).

Example 461: Synthesis of1-[4-(5-Methyl-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: A flask charged with 2-chloro-5-methyl-pyridine (1 g, 7.74mmol), 4-nitro-benzenethiol (1 g, 6.45 mmol), Xantphos (370 mg, 0.64mmol), Pd₂dba₃ (295 mg, 0.32 mmol) and Cs₂CO₃ (4.2 g, 12.9 mmol) indioxane (40 mL) was degassed and filled with N₂. The resulting mixturewas then heated to 100° C. for 16 hrs. The reaction mixture wasconcentrated. The residue was purified by silica gel columnchromatography (PE to PE/EA=20/1 to 5/1) to give5-methyl-2-(4-nitro-phenylsulfanyl)-pyridine (280 mg, yield: 15%) as awhite solid. MS: m/z 246.7 (M+H⁺).

Step 2: To a cooled mixture of5-methyl-2-(4-nitro-phenylsulfanyl)-pyridine (280 mg, 1.13 mmol) in DCM(50 mL) at 0° C. was added m-CPBA (700 mg, 2.84 mmol) in portions. Afteraddition, the resulting mixture was stirred at room temperature for 14hrs. The mixture was then filtered and the filtrate was washed with aq.Na₂SO₃ (30 mL×2) and concentrated. The residue was purified by prep-TLC(PE/EA=2:1) to give 5-methyl-2-(4-nitro-benzenesulfonyl)-pyridine (125mg, yield: 40%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.57 (s,1H), 8.42 (d, J=8.9 Hz, 2H), 8.26-8.13 (m, 3H), 8.00 (d, J=6.8 Hz, 1H),2.38 (s, 3H). MS: m/z 278.8 (M+H⁺).

Step 3: A mixture of 5-methyl-2-(4-nitro-benzenesulfonyl)-pyridine (125mg, 0.48 mmol), Fe (125 mg, 2.24 mmol) and NH₄Cl (120 mg, 2.24 mmol) inEtOH (20 mL) and water (4 mL) was stirred and heated to 80° C. for 16hrs. The mixture was filtered and the filtrate was concentrated to givethe crude 4-(5-methyl-pyridine-2-sulfonyl)-phenylamine (120 mg, yield:100%) as a yellow solid. MS: m/z 248.8 (M+H⁺).

Step 4: To a mixture of 4-(5-methyl-pyridine-2-sulfonyl)-phenylamine(120 mg, 0.48 mmol) and TEA (0.14 mL, 0.96 mmol) in DCM (12 mL) wasadded phenyl chloroformate (113 mg, 0.72 mmol) dropwise. After addition,the resulting mixture was stirred at room temperature for 16 hrs. Thereaction mixture was concentrated. The residue was purified by prep-TLC(PE/EA=1/1) to give [4-(5-methyl-pyridine-2-sulfonyl)-phenyl]-carbamicacid phenyl ester (40 mg, yield: 23%) as a white solid. MS: m/z 368.8(M+H⁺).

Step 5: A mixture of [4-(5-methyl-pyridine-2-sulfonyl)-phenyl]-carbamicacid phenyl ester (40 mg, 0.11 mmol), C-(1H-pyrazol-4-yl)-methylamine(22 mg, 0.22 mmol) and TEA (33 mg, 0.33 mmol) in MeCN (5 mL) was heatedto reflux for 16 hrs. The reaction mixture was concentrated. The residuewas purified by prep-TLC (DCM/MeOH=10/1) and prep-HPLC (TFA system) togive1-[4-(5-methyl-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(7 mg, yield: 17%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (s,1H), 8.05 (d, J=8.1 Hz, 1H), 7.92-7.80 (m, 3H), 7.68-7.49 (m, 4H), 4.28(s, 2H), 2.40 (s, 3H). MS: m/z 372.0 (M+H⁺).

Example 462: Synthesis of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.80 (d, J=2.1 Hz, 1H), 8.36 (d, J=6.1 Hz,2H), 8.08 (dd, J=8.3, 2.4 Hz, 1H), 7.77 (d, J=8.9 Hz, 2H), 7.53 (d,J=8.9 Hz, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.28 (d, J=5.9 Hz, 2H), 4.35 (s,2H), 2.49 (s, 3H). MS: m/z 382.9 (M+H⁺).

Example 463: Synthesis of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a mixture of 6-methyl-pyridine-3-thiol (580 mg, 4.63 mmol)and 1-fluoro-4-nitro-benzene (650 mg, 4.63 mmol) in DMF (15 mL) wasadded Cs₂CO₃ (3 g, 9.26 mmol). The resulting mixture was then heated to60° C. for 6 hrs. The mixture was then poured into water (50 mL) andextracted with EA (30 mL×3). The combined organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography (PE/EA=4/1) to give2-methyl-5-(4-nitro-phenylsulfanyl)-pyridine (385 mg, yield: 34%) as ayellow solid. MS: m/z 246.8 (M+H⁺).

Step 2: To a cooled mixture of2-methyl-5-(4-nitro-phenylsulfanyl)-pyridine (350 mg, 1.42 mmol) in DCM(50 mL) at 0° C. was added m-CPBA (880 mg, 3.54 mmol) in portions. Afteraddition, the resulting mixture was stirred for 10 hrs at roomtemperature The mixture was then filtered and the filtrate was washedwith aq. Na₂SO₃ (30 mL×2) and concentrated. The residue was purifiedcolumn chromatography (PE/EA=4/1) to give2-methyl-5-(4-nitro-benzenesulfonyl)-pyridine (170 mg, yield: 43%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃): δ=9.05 (s, 1H), 8.37 (d, J=8.9Hz, 2H), 8.23-8.01 (m, 3H), 7.34 (d, J=8.2 Hz, 1H), 2.65 (s, 3H). MS:m/z 279.0 (M+H⁺).

Step 3: A mixture of 2-methyl-5-(4-nitro-benzenesulfonyl)-pyridine (170mg, 0.61 mmol), Fe (171 mg, 3.05 mmol) and NH₄Cl (162 mg, 3.05 mmol) inEtOH (25 mL) and water (5 mL) was stirred and heated to 80° C. for 16hrs. The mixture was filtered and the filtrate was concentrated to givethe crude 4-(6-methyl-pyridine-3-sulfonyl)-phenylamine (155 mg, yield:100%) as a yellow solid. MS: m/z 248.9 (M+H⁺).

Step 4: To a mixture of 4-(6-methyl-pyridine-3-sulfonyl)-phenylamine(155 mg, 0.61 mmol) and pyridine (0.2 mL, 2.44 mmol) in DCM (20 mL) wasadded phenyl chloroformate (144 mg, 0.92 mmol) dropwise. After addition,the resulting mixture was stirred at room temperature for 16 hrs. Themixture was diluted with DCM (30 mL), washed with aq. NaHCO₃ and water,dried over Na₂SO₄, filtered and concentrated to give the crude[4-(6-methyl-pyridine-3-sulfonyl)-phenyl]-carbamic acid phenyl ester(220 mg, yield: 98%) as a white solid. MS: m/z 369.1 (M+H⁺).

Step 5: A mixture of [[4-(6-methyl-pyridine-3-sulfonyl)-phenyl]-carbamicacid phenyl ester (70 mg, 0.2 mmol), C-(1H-pyrazol-4-yl)-methylamine (37mg, 0.4 mmol) and TEA (62 mg, 0.6 mmol) in MeCN (15 mL) was heated toreflux for 2 hrs. The reaction mixture was concentrated. The residue waspurified by prep-TLC (DCM/MeOH=10/1) and prep-HPLC (TFA system) to give1-[4-(6-methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(12 mg, yield: 16%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.95(d, J=2.1 Hz, 1H), 8.25 (dd, J=8.3, 2.3 Hz, 1H), 7.87 (d, J=8.9 Hz, 2H),7.72 (s, 2H), 7.61 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.3 Hz, 1H), 4.30 (s,2H), 2.61 (s, 3H). MS: m/z 371.9 (M+H⁺).

Example 464: Synthesis of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.92 (d, J=2.0 Hz, 1H), 8.19 (dd, J=8.3, 2.4Hz, 1H), 8.16 (s, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.63 (d, J=8.9 Hz, 2H),7.48 (d, J=8.2 Hz, 1H), 7.05 (s, 1H), 4.48 (s, 2H), 2.61 (s, 3H). MS:m/z 372.9 (M+H⁺).

Example 465: Synthesis of1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.69 (d, J=2.4 Hz, 1H), 8.46 (d, J=5.9 Hz,2H), 8.06 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.61 (d,J=8.8 Hz, 2H), 7.38 (d, J=5.5 Hz, 2H), 6.88 (d, J=8.8 Hz, 1H), 4.45 (s,2H), 3.96 (s, 3H). MS: m/z 399.0 (M+H⁺).

Example 466: Synthesis of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: A flask charged with 4-acetamidobenzenesulfinic acid sodium salt(2 g, 7.8 mmol), 2-methoxyl-5-pyridineboric acid (1.8 g, 11.7 mmol), TEA(4.4 mL, 31.2 mmol) and Cu(OAc)₂ (1.7 g, 9.36 mmol) in dioxane (50 mL)and DMSO (50 mL) was degassed and filled with N₂. The resulting mixturewas then heated to 65° C. for 16 hrs. Dioxane was evaporated and theresidue was diluted with water (150 mL) and NH₃.H₂O (20 mL), extractedwith EA (50 ml×3) and concentrated. The residue was purified by silicagel column chromatography (PE/EA=5/1 to 1/1) to giveN-[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-acetamide (670 mg, yield:28%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=8.73 (d, J=1.6 Hz,1H), 8.01-7.94 (m, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.67 (d, J=7.9 Hz, 2H),7.50-7.45 (m, 1H), 6.80 (d, J=9.3 Hz, 1H), 3.98 (s, 3H), 2.22 (s, 3H).MS: m/z 307.1 (M+H⁺).

Step 2: A mixture ofN-[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-acetamide (370 mg, 1.2mmol) in HCl (conc., 2 mL) and MeOH (4 mL) was stirred at roomtemperature for 12 hrs. The mixture was diluted with EA (5 mL) andfiltered to give 4-(6-methoxy-pyridine-3-sulfonyl)-phenylamine (200 mg,yield: 63%) as a white solid. MS: m/z 264.9 (M+H⁺).

Step 3: To a mixture of 4-(6-methoxy-pyridine-3-sulfonyl)-phenylamine(200 mg, 0.75 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (30 mL) wasadded phenyl chloroformate (178 mg, 1.13 mmol) dropwise. After addition,the resulting mixture was stirred at room temperature for 16 hrs. Themixture was diluted with DCM (30 mL), washed sequentially with sat.NaHCO₃, aq. CuSO₄ and water, dried over Na₂SO₄, filtered andconcentrated to give the crude[[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-carbamic acid phenyl ester(290 mg, yield: 100%) as a white solid. MS: m/z 385.0 (M+H⁺).

Step 4: A mixture of[[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-carbamic acid phenyl ester(290 mg, 0.75 mmol), C-(1H-pyrazol-4-yl)-methylamine (100 mg, 1.0 mmol)and TEA (0.32 mL, 2.25 mmol) in MeCN (40 mL) was heated to 80° C. for 4hrs. The reaction mixture was concentrated. The residue was purified byprep-HPLC (NH₃.H₂O system) to give1-[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(90 mg, yield: 31%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.69(d, J=2.5 Hz, 1H), 8.06 (dd, J=8.8 Hz, 2.6 Hz, 1H), 7.82 (d, J=8.9 Hz,2H), 7.64-7.48 (m, 4H), 6.88 (d, J=8.9 Hz, 1H), 4.28 (s, 2H), 3.97 (s,3H). MS: m/z 388.1 (M+H⁺).

Example 467: Synthesis of1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.28(s, 1H), 8.12 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.60(d, J=9.2 Hz, 2H), 7.00-6.97 (m, 2H), 6.85 (t, J=6.0 Hz, 1H), 4.36 (d,J=4.2 Hz, 2H), 3.92 (s, 3H). MS: m/z 388.9 (M+H⁺).

Example 468: Synthesis of1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.37 (s, 1H), 9.87 (s, 1H), 8.82 (d, J=6.0Hz, 2H), 8.04 (d, J=2.4 Hz, 1H), 7.89 (d, J=6.4 Hz, 2H), 7.81 (d, J=8.4Hz, 2H), 7.67-7.62 (m, 3H), 7.39 (t, J=6.0 Hz, 1H), 6.40 (d, J=10 Hz,1H), 4.58 (d, J=6.0 Hz, 2H). MS: m/z 384.9 (M+H⁺)

Example 469: Synthesis of1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(6-hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.56-12.38 (m, 2H), 9.04 (s, 1H), 8.04 (s,1H), 7.78 (d, J=8.0 Hz, 2H), 7.67-7.50 (m, 5H), 6.59-6.57 (m, 1H), 6.40(d, J=10 Hz, 1H), 4.16-4.13 (m, 2H). MS: m/z 372.0 (M−H)

Example 470: Synthesis of1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

To a solution of1-[4-(6-methoxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea(105 mg, 0.28 mmol) in MeOH (2 mL) was added HCl (12 N, 1 mL). Thereaction mixture was stirred at 65° C. overnight. The reaction wascompleted detected by LC-MS. The reaction was concentrated and purifiedby prep-HPLC (5-95%; NH₄HCO₃) to afford1-[4-(6-hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea(80 mg, yield 80%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.30(s, 1H), 8.28 (s, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H),7.66-7.60 (m, 3H), 7.01-6.98 (m, 2H), 6.39 (d, J=9.6 Hz, 1H), 4.37 (d,J=6.4 Hz, 2H). MS: m/z 375.1 (M+H⁺).

Example 471: Synthesis of1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(6-chloro-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=9.39 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.49 (d,J=6.0 Hz, 2H), 8.34-8.32 (m, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.4Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.27 (d, J=6.0 Hz, 2H), 6.99 (t, J=6.0Hz, 1H), 4.33 (d, J=6.4 Hz, 2H). MS: m/z 402.9 (M+H⁺)

Example 472: Synthesis of1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The solution of1-[4-(6-hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea(80 mg, 0.267 mmol) and POCl₃ (3 mL) was stirred at 90° C. for 2 hrs.The reaction was cooled and concentrated. The residue was purified byprep-HPLC (5-95; NH₄HCO₃) to affored1-[4-(6-chloro-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea (30mg, yield 29%) as a white solid ¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (s,1H), 8.95 (d, J=2.0 Hz, 1H), 8.35-8.32 (m, 1H), 8.28 (s, 1H), 7.88 (d,J=8.8 Hz, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.01 (s,1H), 6.88 (t, J=5.8 Hz, 1H), 4.37 (d, J=5.2 Hz, 2H). MS: m/z 392.9(M+H⁺)

Example 473: Synthesis of1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(5-chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.63-8.62 (m, 1H), 8.47-8.45 (m, 2H),8.17-8.09 (m, 2H), 7.89-7.87 (m, 2H), 7.64-7.62 (m, 2H), 7.38 (d, J=6.0Hz, 2H), 4.45 (s, 2H). MS: m/z 402.9 (M+H⁺).

Example 474: Synthesis of1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a solution of 2, 5-dichloro-pyridine (1 g, 6.75 mmol) in DMF(10 mL) was added 4-amino-benzenethiol (0.845 g, 6.75 mmol), K₂CO₃ (1.87g, 13.5 mmol), Zn (0.88 g, 13.5 mmol) and NaOH (aq) (2 mL). The reactionmixture was stirred at 80° C. under N₂ overnight. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (40mL) and extracted with EA (40 mL×3). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash column (PE/EA=5/1) to give4-(5-chloro-pyridin-2-ylsulfanyl)-phenylamine (1.2 g, yield: 76%) asyellow oil. ¹H NMR (400 MHz, CDCl₃): δ=8.35 (d, J=2.4 Hz, 1H), 7.39-7.36(m, 3H), 6.74-6.71 (m, 3H). MS: m/z 237.1 (M+H⁺)

Step 2: To a solution of 4-(5-chloro-pyridin-2-ylsulfanyl)-phenylamine(0.5 g, 2.1 mmol) in DCM (60 mL) was added pyridine (0.5 g, 6.3 mmol)and phenyl chloroformate (0.439 g, 3.1 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 hrs. The reaction wascompleted detected by TLC. The reaction was concentrated and purified byflash column (PE/EA=2/1) to give[4-(5-chloro-pyridin-2-ylsulfanyl)-phenyl]-carbamic acid phenyl ester(0.575 g, yield: 76%) as a white solid.

Step 3: To a solution of[4-(5-chloro-pyridin-2-ylsulfanyl)-phenyl]-carbamic acid phenyl ester(0.4 g, 1.12 mmol) in DCM (10 mL) was added m-CPBA (0.831 g, 3.37 mmol,70% wt) at room temperature The solution was stirred at room temperatureovernight. The reaction was completed detected by TLC. The reaction wasquenched with Na₂SO₃ aqueous (10 mL) and extracted with DCM (20 mL×3).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash column (PE to PE/EA=2/1)to give [4-(5-chloro-pyridine-2-sulfonyl)-phenyl]-carbamic acid phenylester (0.371 g, yield: 85%) as a white solid. ¹H NMR (400 MHz, CDCl₃):δ=8.59 (d, J=2.4 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.03-8.00 (m, 2H),7.88 (dd, J₁=8.4 Hz, 2.4 Hz, 1H), 7.63 (d, J=9.2 Hz, 2H), 7.43-7.39 (m,2H), 7.29-7.25 (m, 1H), 7.18-7.16 (m, 2H).

Step 4: To a solution of[4-(5-chloro-pyridine-2-sulfonyl)-phenyl]-carbamic acid phenyl ester(170 mg, 0.438 mmol) in ACN (5 mL) was added TEA (133 mg, 1.31 mmol) andC-(1H-Pyrazol-4-yl)-methylamine (64 mg, 0.657 mmol). The reactionmixture was stirred at 80° C. under N₂ for 2 hrs. The reaction wascompleted detected by LC-MS. The reaction was concentrated and purifiedby prep-TLC (DCM/MeOH=10/1) and prep-HPLC (5-95; NH₄HCO₃) to afford1-[4-(5-chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(15 mg, yield: 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=12.56(s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.16 (d, J=8.0 Hz,1H), 7.81 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.53 (d, J=0.8 Hz,2H), 6.59 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 391.9(M+H⁺).

Example 475: Synthesis of1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(5-chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, CD₃OD): δ=8.64-8.63 (m, 1H), 8.17-8.14 (m, 2H),8.11-8.09 (m, 1H), 7.89-7.87 (m, 2H), 7.62-7.60 (m, 2H), 7.03 (m, 1H),4.47 (m, 2H). MS: m/z 392.9 (M+H⁺).

Example 476: Synthesis of1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. ¹HNMR (400 MHz, CD₃OD): δ=9.326 (s, 1H), 8.821 (s, 1H), 8.69 (s, 1H), 8.48(d, J=5.1 Hz, 2H), 7.942 (d, J=8.7 Hz, 2H), 7.675 (d, J=8.7 Hz, 2H),7.405 (d, J=5.1 Hz, 2H), 4.46 (s, 2H). MS: m/z 369.9 (M+H⁺).

Example 477: Synthesis of1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a mixture of 2-chloro-pyrazine (1 g, 8.8 mmol) and4-Amino-benzenethiol (1.6 g, 13.2 mmol) in DMF (50 mL) was added Cs₂CO₃(5.7 g, 17.6 mmol) and CuI (334 mg, 1.76 mmol). The resulting mixturewas then heated to 80° C. and stirred overnight. The resultant wascooled to room temperature The reaction mixture was concentrated. Theresidue was diluted with water (10 mL) and EA (15 mL), separated andextracted with EA (20 ml×3). The combined organic layer was dried overNa₂SO₄, filtered and concentrated. The resultant was purified by silicagel column chromatography (PE/EA=2/1) to give4-(pyrazin-2-ylsulfanyl)-phenylamine (1.02 g, yield: 56%) as a yellowsolid. MS: m/s 204.0 (M+H⁺).

Step 2: To a solution of 4-(pyrazin-2-ylsulfanyl)-phenylamine (900 mg,4.4 mmol) and pyridine (700 mg, 8.8 mmol) in DCM (10 mL) was addedphenyl chloroformate (1 g, 6.6 mmol) droppwise at 0° C. The mixture wasstirred at room temperature for 2 hrs. The mixture was washed with waterand extracted with DCM (20 ml×3), The organic layers were dried withNa₂SO₄ and concentrated. The resultant was purified by silica gel columnchromatography (PE:EA=5:1) to give[4-(pyrazin-2-ylsulfanyl)-phenyl]-carbamic acid phenyl ester (510 mg,yield: 37%) as white solid. MS: m/z 324.0 (M+H⁺).

Step 3: To a mixture of [4-(pyrazin-2-ylsulfanyl)-phenyl]-carbamic acidphenyl ester (100 mg, 0.31 mmol) in ACN (5 mL) was addedc-(1-ethyl-pyrrolidin-2-yl)-methylamine (90 mg, 0.93 mmol), and TEA(156.6 mg, 1.55 mmol). The resulting mixture was then heated to 80° C.and stirred overnight. The resultant was cooled to room temperature Theresulting mixture was concentrated and purified by prep-TLC(DCM/MeOH=10/1) to give1-[4-(pyrazin-2-ylsulfanyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. (80mg, yield: 79%) as a white solid.

Step 4: To a solution of1-[4-(pyrazin-2-ylsulfanyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea (80mg, 0.245 mmol) in THF (2 mL) was added Oxone (300 mg in 2 ml water,0.49 mmol). The mixture was stirred at room temperature for 4 hrs. Tothe mixture was added Na₂SO₃ (sat., aq., 2 mL) and continue to stir for10 min and then filtered and extracted with EA (20 ml×3). The combinedorganic layer was dried over Na₂SO₄ and concentrated. The resultant waspurified by prep-HPLC to give1-[4-(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea (2.0mg, yield: 2%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=9.16 (s,1H), 8.81 (s, 1H), 8.68 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8Hz, 4H), 4.28 (s, 2H). MS: m/z 359.0 (M+H⁺).

Example 478: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(pyrazine-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. ¹HNMR (400 MHz, CD₃OD): δ=9.32 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.14(s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.03 (s, 1H),4.47 (s, 2H). MS: m/z 359.9 (M+H⁺).

Example 479: Synthesis of1-Pyridin-4-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea

The title compound was prepare using general procedure of 1-[4(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. ¹H NMR(400 MHz, CD₃OD): δ=8.93 (d, J=4.8 Hz, 2H), 8.78 (d, J=6.4 Hz, 2H), 8.05(d, J=6.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.68-7.64 (m, 3H), 4.697 (s,2H). MS: m/z 370.0 (M+H⁺).

Example 480: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. ¹HNMR (400 MHz, CD₃OD): δ=9.93 (d, J=5.2 Hz, 2H), 7.92 (d, J=8.8 Hz, 2H),7.68 (s, 2H), 7.65 (t, J=5.2 Hz, 3H), 4.30 (s, 2H). MS: m/z 358.9(M+H⁺).

Example 481: Synthesis of1-Oxazol-5-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-[4-(pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea. ¹HNMR (400 MHz, CD₃OD): δ=9.93 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 7.93 (d,J=9.2 Hz, 2H), 7.65 (t, J=7.6 Hz, 3H), 7.03 (s, 2H), 4.47 (s, 2H). MS:m/z 359.9 (M+H⁺).

Example 482: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyrimidin-5-ylsulfonyl)phenyl)urea

Step 1: To a solution of 5-bromopyrimidine (2.0 g, 12.6 mmol), Pd₂(dba)₃(577 mg, 0.6 mmol), Xantphos (364 mg, 0.6 mmol) and Cs₂CO₃ (8.2 g, 25.2mmol) in toluene (20 mL) was added 4-aminobenzenethiol (1.7 g, 13.2mmol), and the mixture was stirred at 100° C. under N₂ for 16 hrs. Thereaction mixture was then filtered and the filtrate was concentrated todryness. The residue was purified by reverse flash (ACN/H₂O=5%-95%) togive 4-(pyrimidin-5-ylthio)aniline (640 mg, yield: 25%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d6): δ=8.92 (s, 1H), 8.44 (brs, 2H), 7.26(d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 5.65 (s, 2H).

Step 2: To a solution of 4-(pyrimidin-5-ylthio)aniline (500 mg, 2.5mmol) in pyridine (10 mL) was added phenyl chloroformate (577 mg, 3.7mmol) at 0° C. under N₂, and the mixture was stirred at room temperaturefor 2 hrs. The reaction mixture was concentrated to dryness and theresidue was purified by flash (PE/EA=5%-40%) to give phenyl(4-(pyrimidin-5-ylthio)phenyl)carbamate (680 mg, yield: 86%) as a whitesolid. MS: m/z 324.1 (M+H⁺).

Step 3: To a solution of phenyl (4-(pyrimidin-5-ylthio)phenyl)carbamate(500 mg, 1.5 mmol) in DCM (10 mL) was added m-CPBA (800 mg, 3.0 mmol)and the mixture was stirred at room temperature for 16 hrs. The reactionmixture was diluted with DCM (20 mL) and then washed by saturated Na₂SO₃(20 mL), saturated NaHCO₃ (20 mL) and then concentrated to dryness. Theresidue was purified by flash (PE/EA=5%-40%) to give phenyl(4-(pyrimidin-5-ylsulfonyl)phenyl)carbamate (230 mg, yield: 42%) as awhite solid.

Step 4: To a solution of phenyl(4-(pyrimidin-5-ylsulfonyl)phenyl)carbamate (130 mg, 0.4 mmol) in ACN(10 mL) was added (1H-pyrazol-4-yl)methanamine (109 mg, 1.1 mmol) andTEA (75 mg, 0.7 mmol) and the mixture was stirred at 80° C. for 16 hrs.The reaction solution was concentrated to dryness and the residue waspurified by prep-HPLC (NH₃.H₂O) to give1-((H-pyrazol-4-yl)methyl)-3-(4-(pyrimidin-5-ylsulfonyl)phenyl)urea (48mg, yield: 36%) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ=9.45 (s,1H), 9.34 (d, J=4.4 Hz, 2H), 9.14 (s, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.65(d, J=8.8 Hz, 2H), 7.56 (d, J=4.4 Hz, 2H), 6.64 (t, J=4.8 Hz, 1H), 4.14(d, J=4.8 Hz, 2H). MS: m/z 358.9 (M+H⁺).

Example 483: Synthesis of1-(4-Cyclohexanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-cyclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea. ¹H NMR (400MHz, DMSO-d₆): δ=9.55 (s, 1H), 8.53 (s, 2H), 7.66 (s, 4H), 7.35 (d,J=4.4 Hz, 2H), 7.22 (t, J=5.8 Hz, 1H), 4.37 (d, J=6.0 Hz, 2H), 3.06-3.03(m, 1H), 1.88-1.86 (m, 2H), 1.74-1.73 (m, 2H), 1.57 (d, J=12.0 Hz, 1H),1.26-1.15 (m, 4H), 1.08-1.03 (m, 1H). MS: m/z 374.0 (M+H⁺).

Example 484: Synthesis of1-(4-Cyclohexanesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-yclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea. ¹H NMR (400MHz, CD₃OD): δ=8.30 (s, 2H), 7.69 (dd, J=18.8, 8.8 Hz, 4H), 4.41 (s,2H), 3.03-2.97 (m, 1H), 2.02-1.98 (m, 2H), 1.84-1.82 (m, 2H), 1.67 (d,J=12.4 Hz, 1H), 1.38-1.22 (m, 4H), 1.17-1.10 (m, 1H). MS: m/z 363.0(M+H⁺).

Example 485: Synthesis of1-(4-Cyclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea

Step 1: To a solution of 1-fluoro-4-nitro-benzene (1.00 g, 7.09 mmol) inDMF (20 mL) was added cyclohexanethiol (0.99 g, 8.50 mmol), K₂CO₃ (2.94g, 21.27 mmol) and CuI (0.14 g, 0.71 mmol). The reaction mixture wasstirred at 140° C. under N₂ for 4 hrs. The reaction was completeddetected by LC-MS. The reaction was quenched with water (5 mL) andextracted with DCM (20 mL×3). The combined organic layer was washed withbrine (20 mL) and water (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silia gel chromatography (PEto PE/EA=20/1) to give 1-Cyclohexylsulfanyl-4-nitro-benzene (1.60 g,yield 95%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.15-8.12 (m,2H), 7.54-7.50 (m, 2H), 3.63-3.57 (m, 1H), 2.01-1.97 (m, 2H), 1.74-1.71(m, 2H), 1.63-1.58 (m, 1H), 1.47-1.34 (m, 4H), 1.31-1.26 (m, 1H).

Step 2: To a solution of 1-cyclohexylsulfanyl-4-nitro-benzene (1.60 g,6.74 mmol) in DCM (30 mL) was added m-CPBA (5.46 g, 26.9 mmol, 85% Wt)at 0° C. The reaction mixture was allowed to warm to room temperaturefor 4 hrs. The reaction was completed detected by LC-MS. The reactionwas quenched with Na₂SO₃ aqueous (10 mL) and extracted with DCM (20mL×3). The combined organic layer was washed with NaHCO₃ aqueous (20 mL)and water (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silia gel chromatography (PE to PE/EA=10/1) togive 1-cyclohexanesulfonyl-4-nitro-benzene (1.50 g, yield: 82%) as awhite solid. MS: m/z 270.1 (M+H⁺).

Step 3: To a solution of 1-cyclohexanesulfonyl-4-nitro-benzene (1.50 g,5.57 mmol) in MeOH (30 mL) was added Pd/C (0.15 g, 10% Wt). The reactionmixture was stirred at room temperature under H₂ overnight. The reactionwas completed detected by LC-MS. After filtration via filter paper, theorganic layer was concentrated under pressure to give4-cyclohexanesulfonyl-phenylamine (1.26 g, yield: 95%) as a gray solid.¹H NMR (300 MHz, DMSO-d₆): δ=7.13-7.39 (m, 2H), 6.72-6.68 (m, 2H), 6.29(br s, 2H), 2.95-2.86 (m, 1H), 1.88-1.85 (m, 2H), 1.84-1.83 (m, 2H),1.74-1.72 (m, 1H), 1.22-1.14 (m, 5H).

Step 4: To a solution of 4-cyclohexanesulfonyl-phenylamine (1.25 g, 5.20mmol) in DCM (30 mL) was added pyridine (1.23 g, 15.60 mmol) and phenylchloroformate (1.63 g, 10.40 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 1 hr. The reaction was completeddetected by LC-MS. The reaction was quenched with water (5 mL) andextracted with DCM (20 mL×3). The combined organic layer was washed withbrine (20 mL) and water (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by re-crystallization from etherabsolute (10 mL) to give (4-cyclohexanesulfonyl-phenyl)-carbamic acidphenyl ester (0.79 g, yield: 44%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ=10.78 (s, 1H), 7.80-7.74 (m, 4H), 7.49-7.43 (m, 2H),7.31-7.25 (m, 3H), 3.13-3.08 (m, 1H), 1.88-1.84 (m, 2H), 1.79-1.74 (m,2H), 1.58 (d, J=11.2 Hz, 1H), 1.28-1.16 (m, 4H), 1.07-1.02 (m, 1H).

Step 5: To a solution of (4-cyclohexanesulfonyl-phenyl)-carbamic acidphenyl ester (30.0 mg, 0.08 mmol) in ACN (20 mL) was added TEA (40.5 mg,0.40 mmol) and c-oxazol-5-yl-methylamine (21.5 mg, 0.16 mmol). Thereaction mixture was stirred at 80° C. for 4 hrs. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (5 mL)and extracted with DCM (20 mL×3). The combined organic layers werewashed with brine (20 mL) and water (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by prep.HPLC to give1-(4-cyclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea (20.9 mg,yield 69%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.84 (s, 1H),9.30 (s, 1H), 7.65 (s, 4H), 7.24 (t, J=11.6 Hz, 1H), 7.03 (s, 1H), 4.39(d, J=5.6 Hz, 2H), 3.06-3.03 (m, 1H), 1.88-1.83 (m, 2H), 1.78-1.69 (m,2H), 1.58 (d, J=12.0 Hz, 1H), 1.26-1.15 (m, 4H), 1.09-1.02 (m, 1H). MS:m/z 364.0 (M+H⁺).

Example 486: Synthesis of1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.35 (s, 1H), 8.51-8.50 (m, 2H), 7.67 (s,4H), 7.29 (d, J=5.6 Hz, 2H), 6.98 (s, 1H), 4.35 (d, J=5.6 Hz, 2H),3.07-3.01 (m, 1H), 2.81-2.78 (m, 2H), 2.11 (s, 3H), 1.84-1.75 (m, 4H),1.48-1.45 (m, 2H). MS: m/z 389.0 (M+H⁺).

Example 487: Synthesis of1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, CD₃OD): δ=8.26 (s, 2H), 7.78-7.71 (m, 4H), 4.39 (s,2H), 3.60 (d, J=11.6 Hz, 2H), 3.48-3.41 (m, 1H), 3.05-2.99 (m, 2H), 2.84(s, 3H), 2.22-2.20 (m, 2H), 1.96-1.93 (m, 2H). MS: m/z 378.0 (M+H⁺).

Example 488: Synthesis of1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

Step 1: To a mixture of 4-oxo-piperidine-1-carboxylic acid tert-butylester (20 g, 0.15 mol) in MeOH (100 mL) was added NaBH₄ (14.25 g, 0.75mol) at 0° C. slowly. The reaction mixture was allowed to warm to roomtemperature overnight. The mixture was quenched with NH₄Cl (100 mL) andextracted with DCM (200 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated to give4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (19 g, yield95%) as yellow solid. MS: m/z 202.0 (M+H⁺).

Step 2: To a mixture of 4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester (19.0 g, 0.095 mol) in DCM (200 mL) was added TEA(19.19 g, 0.19 mol) and MsCl (21 g, 0.19 mol) at 0° C. slowly. Thereaction mixture was allowed to warm to room temperature overnight. Themixture was washed with H₂O (100 mL×3) and extracted with DCM (200mL×3). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated to give4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (20g, yield 76%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ=4.89-4.88(m, 1H), 3.72-3.67 (m, 2H), 3.33-3.29 (m, 2H), 3.27 (s, 3H), 1.97-1.94(m, 2H), 1.84-1.79 (m, 2H), 1.46 (s, 9H).

Step 3: To a mixture of 4-methanesulfonyloxy-piperidine-1-carboxylicacid tert-butyl ester (5 g, 32 mmol) in DMF (25 mL) was added4-nitro-benzenethiol (13.4 g, 48 mmol) and K₂CO₃ (8.8 g, 64 mmol). Themixture was stirred at 100° C. overnight. The mixture was washed H₂O(100 mL×5) and extracted with EA (100 mL×5). The combined organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography (PE/EA=20/1) to give4-(4-nitro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester(3.38 g, yield 31%) as a yellow liquid. MS: m/z 339.0 (M+H⁺).

Step 4: To a mixture of4-(4-nitro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester(3.38 g, 10 mmol) in DCM (50 mL) was added m-CPBA (5.16 g, 30 mmol) at0° C. slowly. Then the mixture was stirred at room temperatureovernight. To the mixture was added Na₂SO₃ and filtered and washed withNaHCO₃. The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified withchromatography (PE/EA=3/1) to give4-(4-nitro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butylester (2.58 g, yield 70%) as a white solid. MS: m/z 371.0 (M+H⁺).

Step 5: A mixture of 4-(4-nitro-benzenesulfonyl)-piperidine-1-carboxylicacid tert-butyl ester (2.58 g, 6.90 mmol) and Pd/C (10% wet, 200 mg) inMeOH (50 mL) was stirred at room temperature under H₂ (1 atm) overnight.The reaction solution was filtered. The filtrate was concentrated togive 4-(4-amino-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butylester (2.1 g, yield 91%) as a white solid. MS: m/z 341.0 (M+H⁺).

Step 6: To a solution of4-(4-amino-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butylester (2.1 g, 6.0 mmol) in DCM (20 mL) was added pyridine (0.96 g, 12mmol) and phenyl chloroformate (1.93 g, 12 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 hrs. The reaction wascompleted detected by LC-MS. The reaction was quenched with water (10mL) and extracted with DCM (10 mL×3). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column (PE/EA=10/1) to give4-(4-phenoxycarbonylamino-benzenesulfonyl)-piperidine-1-carboxylic acidtert-butyl ester (0.46 g, yield 17%) as a white solid. MS: m/z 461.0(M+H⁺).

Step 7: A mixture of4-(4-phenoxycarbonylamino-benzenesulfonyl)-piperidine-1-carboxylic acidtert-butyl ester (0.15 g, 0.3 mmol) in ACN (15 mL) was added TEA (60.6mg, 0.6 mmol) and C-Oxazol-5-yl-methylamine (80 mg, 0.6 mmol). Thereaction mixture was stirred at 80° C. overnight. The reaction wasquenched with water (10 mL) and extracted with DCM (10 mL×3). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel column(DCM/MeOH=20/1) to give4-[4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonyl]-piperidine-1-carboxylicacid tert-butyl ester (120 mg, yield 87%) as a white solid.

Step 8: A solution of4-[4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonyl]-piperidine-1-carboxylicacid tert-butyl ester (120 mg, 0.25 mmol) in HCl/MeOH (3 mL) was stirredat room temperature for 1 hr. The reaction was completed detected byTLC. The mixture was concentrated to give1-oxazol-5-ylmethyl-3-[4-(piperidine-4-sulfonyl)-phenyl]-urea (90 mg,yield 90%) as a white solid.

Step 9: To a mixture of1-oxazol-5-ylmethyl-3-[4-(piperidine-4-sulfonyl)-phenyl]-urea (90 mg,0.25 mmol) and formaldehyde (15 mg, 0.50 mol) in MeOH (10 mL) wasstirred at room temperature for 1 hr. Then to the mixture was addedNaBH₃CN (47 mg, 0.75 mol) and stirred at room temperature overnight. Themixture was purified by prep-HPLC togive1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea(10 mg, yield 11%) as white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.54 (s,1H), 8.29 (s, 1H), 7.72-7.67 (m, 4H), 7.142-7.14 (m, 1H), 7.02 (s, 1H),4.39 (d, J=5.2 Hz, 2H), 3.32 (s, 1H), 3.09-3.06 (m, 2H), 2.81-2.75 (m,2H), 2.62 (s, 3H), 1.99-1.82 (m, 4H). MS: m/z 379.2 (M+H⁺).

Example 489: Synthesis of1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.47 (s, 1H), 8.50 (d, J=6.0 Hz, 2H), 7.66(s, 4H), 7.29 (d, J=5.6 Hz, 2H), 7.11 (s, 1H), 4.33 (d, J=6.0 Hz, 2H),3.06-2.99 (m, 1H), 2.81-2.78 (m, 2H), 2.67-2.54 (m, 1H), 2.05-2.03 (m,2H), 1.81-1.79 (m, 2H), 1.39-1.35 (m, 2H), 0.89 (d, J=6.0 Hz, 6H). MS:m/z 417.0 (M+H⁺).

Example 490: Synthesis of1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, CD₃OD): δ=7.73 (d, J=8.8 Hz, 2H), 7.66-7.64 (m, 4H),4.30 (s, 2H), 3.09-2.98 (m, 3H), 2.76-2.70 (m, 1H), 2.23-2.21 (m, 2H),1.98-1.96 (m, 2H), 1.72-1.62 (m, 2H), 1.04 (d, J=6.4 Hz, 6H). MS: m/z406.1 (M+H⁺).

Example 491: Synthesis of1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (300 MHz, DMSO-d₆): δ=9.24 (s, 1H), 8.29 (s, 1H), 7.64 (s, 4H),7.01 (s, 1H), 6.91 (s, 1H), 4.38 (d, J=5.7 Hz, 2H), 3.34-3.32 (m, 1H),2.82-2.76 (m, 2H), 2.68-2.60 (m, 1H), 2.08-1.99 (m, 2H), 1.81-1.76 (m,2H), 1.39-1.34 (m, 2H), 0.89 (s, 6H). MS: m/z 407.1 (M+H⁺).

Example 492: Synthesis of1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, CD₃OD): δ=8.48-8.46 (m, 2H), 7.76-7.66 (m, 4H), 7.40(d, J=6.0 Hz, 2H), 4.47 (s, 2H), 3.31-3.30 (m, 3H), 2.11-1.94 (m, 9H),0.88 (d, J=6.4 Hz, 6H). MS: m/z 431.0 (M+H⁺).

Example 493: Synthesis of1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (400 MHz, CD₃OD): δ=7.71-7.69 (m, 2H), 7.63-7.61 (m, 2H), 7.57(s, 2H), 4.28 (s, 2H), 3.03-2.92 (m, 3H), 2.04-2.02 (m, 2H), 1.89-1.83(m, 4H), 1.78-1.63 (m, 3H), 0.84 (d, J=6.4 Hz, 6H). MS: m/z 420.0(M+H⁺).

Example 494: Synthesis of1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (300 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.29 (s, 1H), 7.65 (s, 4H),7.01 (s, 1H), 6.90-6.89 (m, 1H), 4.38-4.36 (m, 2H), 3.13-2.77 (m, 3H),1.79-1.74 (m, 9H), 0.79 (d, J=4.2 Hz, 6H). MS: m/z 421.0 (M+H⁺).

Example 495: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

Step 1: A mixture of 4-(4-nitro-benzenesulfonyl)-piperidine-1-carboxylicacid tert-butyl ester (1.8 g, 4.8 mmol) in DCM/TFA (30 mL/6 mL) wasstirred at room temperature overnight. The mixture was concentrated togive 4-(4-nitro-benzenesulfonyl)-piperidine (1.8 g, yield 1000%) as awhite solid. MS: m/z 271.0 (M+H⁺).

Step 2: A mixture of 4-(4-nitro-benzenesulfonyl)-piperidine (1.80 g, 67mmol) and tetrahydro-pyran-4-one (1.3 g, 13 mmol) in MeOH (30 mL) wasstirred at room temperature for 1 hr. Then NaBH₃CN (1.26 g, 0.02 mol)was added and the mixture was stirred at room temperature overnight. Themixture was purified by silica gel chromatography (PE/EA=20/1) to give4-(4-nitro-benzenesulfonyl)-1-(tetrahydro-pyran-4-yl)-piperidine (200mg, yield 8%) as a white solid. MS: m/z 355.0 (M+H⁺).

Step 3: A mixture of4-(4-nitro-benzenesulfonyl)-1-(tetrahydro-pyran-4-yl)-piperidine (200mg, 0.56 mmol), iron (94.92 mg, 1.69 mmol) and NH₄Cl (90.39 mg, 1.69mol) in EtOH/H₂O (5 mL/2 mL) was stirred at 90° C. overnight. Thereaction was completed detected by LC-MS. The mixture was filtered andextracted with EA (30 mL×3). The organic layer was washed with brined(30 mL), dried over Na₂SO₄, filtered and concentrated to give the crude4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenylamine (100 mg,yield 55%) as a yellow solid. MS: m/z 325.0 (M+H⁺).

Step 4: To a mixture of4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenylamine (100 mg,0.3 mmol) and pyridine (48 mg, 0.6 mmol) in DCM (5 mL) was added phenylchloroformate (93 mg, 0.6 mmol) dropwise at 0° C. The reaction mixturewas allowed to warm to room temperature for 1 hr. The reaction wascompleted detected by LC-MS. The combined organic layer was washed withbrine (5 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas was purified by prep-TLC (DCM/MeOH=20/1) to give{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-carbamicacid phenyl ester (50 mg, yield 37%) as a white solid. MS: m/z 445.0(M+H⁺).

Step 5: To a solution of{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-carbamicacid phenyl ester (50 mg, 0.112 mmol) and TEA (34 mg g, 0.337 mmol) inACN (10 mL) was added c-pyridin-4-yl-methylamine (36.45 mg, 0.337 mmol).The reaction was stirred at 0° C. for 1 h. Then the reaction mixture wasconcentrated in vacuum. The residue was purified by prep-HPLC to give1-pyridin-4-ylmethyl-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea(3.5 mg, yield: 7%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47(d, J=5.2 Hz, 2H), 7.76-7.66 (m, 4H), 7.4 (d, J=5.6 Hz, 2H), 4.47 (s,2H), 3.98-3.95 (m, 2H), 3.39-3.36 (m, 2H), 3.17-3.14 (m, 3H), 2.60 (s,1H), 2.28 (s, 2H), 2.03-2.0 (m, 2H), 1.79-1.68 (m, 6H). MS: m/z 459.0(M+H⁺)

Example 496: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

The title compound was prepared using general procedure of1-(h-pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea.H NMR (400 MHz, CD₃OD): δ=7.73 (d, J=8.8 Hz, 2H), 7.66-7.60 (m, 4H),4.30 (s, 2H), 3.96-3.93 (m, 2H), 3.38-3.31 (m, 2H), 3.08-3.06 (m, 3H),2.49-2.45 (m, 1H), 2.19-2.13 (m, 2H), 1.75-1.48 (m, 8H). MS: m/z 448.0(M+H⁺).

Example 497: Synthesis of1-Oxazol-5-ylmethyl-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea

The title compound was prepared using general procedure of1-(1H-pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea.¹H NMR (400 MHz, CD₃OD): δ=8.16 (s, 1H), 7.70 (d, J=9.2 Hz, 2H),7.67-7.64 (m, 2H), 7.04 (s, 1H), 4.48 (s, 2H), 3.96-3.93 (m, 2H),3.35-3.30 (m, 2H), 3.09-3.06 (m, 3H), 2.51-2.43 (m, 1H), 2.21-2.14 (m,2H), 1.99-1.95 (m, 2H), 1.77-1.49 (m, 6H). MS: m/z 449.0 (M+H⁺).

Example 498: Synthesis of1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl) phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.31 (s, 1H), 8.48 (d, J=6 Hz, 2H), 8.11(s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.89 (d, J=8.4 Hz, 3H), 7.71-7.67 (m,3H), 7.62 (d, J=8.8 Hz, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.44 (t, J=7.6 Hz,1H), 7.26 (d, J=5.6 Hz, 2H), 6.96-6.93 (m, 1H), 4.32 (d, J=6.0 Hz, 2H).MS: m/z 444.0 (M+H⁺).

Example 499: Synthesis of 1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-3-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl) phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.59 (s, 1H), 9.17 (s, 1H), 8.10 (s, 1H),7.94 (d, J=7.6 Hz, 1H), 7.88-7.87 (m, 3H), 7.71-7.67 (m, 3H), 7.61-7.49(m, 6H), 7.44 (t, J=7.2 Hz, 1H), 6.63 (t, J=5.6 Hz, 1H), 4.14 (d, J=5.6Hz, 2H). MS: m/z 433.0 (M+H⁺).

Example 500: Synthesis of1-(4-([1,1′-Biphenyl]-3-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl) phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H),7.95 (d, J=7.2 Hz, 1H), 7.89-7.87 (m, 3H), 7.71-7.67 (m, 3H), 7.60 (d,J=8.8 Hz, 2H), 7.53-7.49 (m, 2H), 7.46-7.44 (m, 1H), 6.99 (s, 1H),6.85-6.82 (m, 1H), 4.36 (d, J=5.2 Hz, 2H). MS: m/z 434.0 (M+H⁺).

Example 501: Synthesis of1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 2-bromobenzenethiol (1 g, 5.32 mmol) and1-fluoro-4-nitrobenzene (1.12 g, 7.98 mmol) in DMF (10 mL) was addedK₂CO₃ (2.2 g, 15.96 mmol). The reaction was stirred at 80° C. overnight.Then DMF was removed in vacuum. The residue was purified by flash column(PE) to give (2-bromophenyl) (4-nitrophenyl) sulfane as a white solid(1.6 g, yield: 97.5%). ¹H NMR (300 MHz, CDCl₃): δ=8.16-8.11 (m, 2H),7.77-7.74 (m, 1H), 7.60-7.56 (m, 1H), 7.42-7.35 (m, 2H), 7.42-7.35 (m,2H).

Step 2: To a solution of (2-bromophenyl)(4-nitrophenyl)sulfane (1.6 g,5.17 mmol) in DCM (30 mL) was added m-CPBA (3.15 g, 15.5 mmol) slowly at0° C. The reaction was stirred at room temperature overnight. Thereaction mixture was quenched with Na₂SO₃ (aq). Then the mixture wasconcentrated in vacuum and purified by flash column (PE/EA=10:1) to give1-bromo-2-((4-nitrophenyl) sulfonyl) benzene (1.67 g, yield: 94.6%).

Step 3: To a solution of 1-bromo-2-((4-nitrophenyl)sulfonyl)benzene(2.42 g, 7.09 mmol), phenylboronic acid (1.30 g, 10.6 mmol) and K₂CO₃(2.94 g, 21.2 mmol) in 1, 4-dioxane (50 mL) and water (10 mL) was addedPd(dppf)Cl₂ (259 mg 0.354 mmol). The reaction was stirred at 90° C.under N₂ for 4 hrs. Then 1, 4-dioxane and water was removed in vacuum.The residue was purified by silica gel column (PE/EA=5/1) to give2-((4-nitrophenyl)sulfonyl)-1,1′-biphenyl (1.463 mg, yield: 60%). ¹H NMR(300 MHz, CDCl₃): δ=8.50-8.46 (m, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.68-7.65(m, 2H), 7.40-7.33 (m, 3H), 7.26-7.19 (m, 3H), 6.97 (d, J=7.5 Hz, 2H).

Step 4: To a solution of 2-((4-nitrophenyl) sulfonyl)-1,1′-biphenyl (500mg, 1.47 mmol) in MeOH (5 mL) was added Pd/C (10% wet, 100 mg). Thereaction was stirred at room temperature under H₂ (3 atm) overnight. ThePd/C was filtered. The organic layers were concentrated in vacuum togive 4-([1,1′-biphenyl]-2-ylsulfonyl)aniline as a yellow oil (455 mg,crude), which was used for next step without further purification. MS:m/z 310.1. (M+H⁺).

Step 5: To a solution of 4-([1,1′-biphenyl]-2-ylsulfonyl)aniline (455mg, 0.767 mmol) in DCM (10 mL) was added pyridine (349 mg, 4.4 mmol) andphenyl chloroformate (224 mg, 1.6 mmol) dropwise at 0° C. The reactionwas stirred at room temperature for 2 hrs. The mixture was washed withwater (10 mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuum. The residue was purified by flash column(PE/EA=10/1) to give phenyl(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)carbamate as a colorless oil(473 mg, yield: 74.8%).

Step 6: To a solution of phenyl(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)carbamate (150 mg, 0.35 mmol) inACN (5 mL) was added pyridin-4-ylmethanamine (56.7 mg, 0.52 mmol) andTEA (106 mg, 1.048 mmol). The reaction was stirred at 80° C. for 1.5hrs. The ACN was removed in vacuum. The residue was purified by prep-TLC(DCM/MeOH=10/1) to give1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea(50.4 mg, yield: 36%). ¹H NMR (400 MHz, DMSO-d₆): δ=9.21 (s, 1H), 8.50(d, J=5.6 Hz, 2H), 8.23-8.21 (m, 1H), 7.71-7.67 (m, 2H), 7.38-7.34 (m,3H), 7.29-7.25 (m, 5H), 7.05 (d, J=9.2 Hz, 2H), 6.97 (d, J=7.8 Hz, 2H),6.91 (t, J=6.0 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 444.0 (M+H⁺).

Example 502: Synthesis of 1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl) phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.67 (s, 1H), 9.35 (s, 1H), 8.24-8.21 (m,1H), 7.71-7.67 (m, 2H), 7.53 (s, 2H), 7.38-7.33 (m, 3H), 7.30-7.24 (m,3H), 7.03 (t, J=8.8 Hz, 2H), 6.97 (d, J=7.2 Hz, 2H), 6.78 (t, J=5.2 Hz,1H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 433.1 (M+H⁺).

Example 503: Synthesis of1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.15 (s, 1H), 8.28 (s, 1H), 8.24-8.21 (m,1H), 7.71-7.67 (m, 2H), 7.36-7.33 (m, 3H), 7.29-7.24 (m, 3H), 7.06-7.01(m, 3H), 6.98-6.95 (m, 2H), 6.84 (t, J=6 Hz, 1H), 4.36 (d, J=5.6 Hz,2H). MS: m/z 434.0 (M+H⁺).

Example 504: Synthesis of1-(4-((2′-Methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 1-bromo-2-((4-nitrophenyl)sulfonyl)benzene (400mg, 1.16 mmol) in dioxane/H₂O (48 mL) (v/v, 5:1) was added2-methylphenylboronic acid (477 mg, 3.50 mmol), Pd(PPh₃)₄ (135 mg, 0.12mmol) and potassium carbonate (480 mg, 3.48 mmol). After stirred at 100°C. overnight under balloon Ar atmosphere, the reaction was filtered andthe filtrate was concentrated in vacuum to give a crude product whichwas purified by silica gel column (PE/EA=4/1) to give2-methyl-2′-((4-nitrophenyl)sulfonyl)-1,1′-biphenyl (180 mg, 44%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.41-8.39 (m, 1H), 8.19-8.15(m, 2H), 7.83-7.78 (m, 2H), 7.47-7.44 (m, 2H), 7.30-7.25 (m, 2H),7.08-7.02 (m, 2H), 6.68 (d, J=6.8 Hz, 1H), 1.56 (s, 3H).

Step 2: To a solution of2-methyl-2′-((4-nitrophenyl)sulfonyl)-1,1′-biphenyl (180 mg, 0.51 mmol)in EtOH/H₂O (30 mL) (v/v, 5:1) was added iron (143 mg, 2.55 mmol) andNH₄Cl (135 mg, 2.55 mmol). The reaction mixture was stirred at 80° C.overnight. The reaction was monitored by LCMS and TLC. After completion,the reaction mixture was filtrated and the cake was washed with EtOH.The solvent was concentrated in vacuum to give a crude product, whichwas purified by silica gel column (PE/EA=2/1) to give4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)aniline (140 mg, 85%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆):δ=8.22-8.20 (m, 1H), 7.66-7.62(m, 2H), 7.27-7.25 (m, 1H), 7.17-7.08 (m, 3H), 6.87-6.85 (m, 1H),6.78-6.75 (m, 2H), 6.38-6.36 (m, 2H), 6.08 (s, 2H), 1.51 (s, 3H).

Step 3: To a solution of4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)aniline (140 mg, 0.43 mmol)in DCM (15 mL) was added phenyl chloroformate (312 mg, 2.0 mmol) and TEA(0.5 mL). Then the mixture was stirred at room temperature overnight.The reaction was monitored by TLC and LCMS. After completion, themixture was concentrated in vacuum to give a crude product which waspurified by a silica gel column (PE/EA=2/1) to afford phenyl(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (160 mg,84%) as a white solid.

Step 4: To a solution of phenyl(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (80 mg,0.18 mmol) in ACN (15 mL) was added Pyridin-4-ylmethanamine (25 mg, 0.23mmol) and TEA (0.5 mL). Then the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC and LCMS. After completion,the mixture was concentrated in vacuum to give a residue which waspurified by pre-HPLC to afford1-(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea(34.3 mg, 44%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.24 (s,1H), 8.50 (d, J=6.0 Hz, 2H), 8.29-8.27 (m, 1H), 7.71-7.68 (m, 2H), 7.38(d, J=8.0 Hz, 2H), 7.29-7.25 (m, 3H), 7.21-7.19 (m, 1H), 7.10 (t, J=8.0Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.93 (t, J=6.0 Hz, 1H), 6.80 (d, J=7.0Hz, 1H), 4.33 (d, J=5.6 Hz, 2H), 1.57 (s, 3H). MS: m/z 458.1 (M+H⁺).

Example 505: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

To a solution of [4-(3′-methyl-biphenyl-2-sulfonyl)-phenyl]-carbamicacid phenyl ester (80 mg, 0.18 mmol) in ACN (15 mL) was added(1H-pyrazol-4-yl)methanamine (23 mg, 0.23 mmol) and TEA (0.5 mL). Themixture was stirred at 80° C. overnight. The reaction was monitored byTLC and LCMS. After completion, the mixture was concentrated in vacuumto give a crude product which was purified by prep-TLC (DCM/MeOH=10/1)to afford1-((1H-pyrazol-4-yl)methyl)-3-(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea(33.8 mg, 15%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=12.56 (s,1H), 8.93 (s, 1H), 8.29-8.27 (m, 1H), 7.71-7.67 (m, 2H), 7.53 (s, 2H),7.35 (d, J=8.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.08(m, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.80 (d, J=7.6 Hz, 1H), 6.51 (s, 1H),4.15 (d, J=6.0 Hz, 2H), 1.49 (s, 3H). MS: m/z 447.1 (M+H⁺).

Example 506: Synthesis of1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.51-8.49 (m, 2H), 8.26-8.24(m, 1H), 7.74-7.71 (m, 2H), 7.45-7.41 (m, 3H), 7.33-7.28 (m, 3H),7.18-7.07 (m, 4H), 7.03-6.98 (m, 1H), 6.95-6.92 (m, 1H), 4.33 (d, J=6.0Hz, 2H). MS: m/z 461.7 (M+H⁺).

Example 507: Synthesis of1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepare using genera procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.58 (s, 1H), 8.94 (s, 1H), 8.26-8.24 (m,1H), 7.75-7.70 (m, 2H), 7.55-7.38 (m, 5H), 7.32-7.30 (m, 1H), 7.17-7.08(m, 4H), 7.02-6.98 (m, 1H), 6.52 (t, J=5.6 Hz, 1H), 4.15 (d, J=5.2 Hz,2H). MS: m/z 450.7 (M+H⁺).

Example 508: Synthesis of1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.52-8.50 (m, 2H), 8.23-8.21(m, 1H), 7.73-7.70 (m, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.36-7.28 (m, 4H),7.23-7.18 (m, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.92 (t, J=6 Hz, 1H), 6.82(d, J=7.6 Hz, 1H), 6.75-6.72 (m, 1H), 4.33 (d, J=5.6 Hz, 2H). MS: m/z462.1 (M+H⁺).

Example 509: Synthesis of1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 8.96 (s, 1H), 8.22 (d, J=7.2Hz, 1H), 7.74-7.68 (m, 2H), 7.56-7.37 (m, 4H), 7.35-7.28 (m, 2H),7.23-7.18 (m, 1H), 7.10 (d, J=8.8 Hz, 2H), 6.81 (d, J=6.8 Hz, 1H), 6.73(d, J=9.2 Hz, 1H), 6.53 (t, J=5.2 Hz, 1H), 4.14 (d, J=4.8 Hz, 2H). MS:m/z 450.8 (M+H⁺).

Example 510: Synthesis of1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.23 (s, 1H), 8.51-8.49 (m, 2H), 8.23-8.21(m, 1H), 7.72-7.68 (m, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.29-7.25 (m, 3H),7.13-7.08 (m, 4H), 7.02-6.98 (m, 2H), 6.91 (t, J=6.0 Hz, 1H), 4.32 (d,J=6.0 Hz, 2H). MS: m/z 461.8 (M+H⁺).

Example 511: Synthesis of1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.49 (s, 1H), 8.95 (s, 1H), 8.23-8.21 (m,1H), 7.73-7.68 (m, 2H), 7.53 (s, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.27-7.25(m, 1H), 7.13-7.06 (m, 4H), 7.01-6.98 (m, 2H), 6.53 (t, J=5.6 Hz, 1H),4.14 (d, J=5.6 Hz, 2H). MS: m/z 450.7 (M+H⁺).

Example 512: Synthesis of1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.22 (s, 1H), 8.50 (d, J=5.2 Hz, 2H), 8.24(d, J=7.2 Hz, 1H), 7.71-7.65 (m, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.28 (d,J=4.8 Hz, 2H), 7.24-7.14 (m, 3H), 7.03 (d, J=8.4 Hz, 2H), 6.91 (t, J=5.6Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 6.50 (s, 1H), 4.33 (d, J=5.2 Hz, 2H),2.18 (s, 3H). MS: m/z 457.8 (M+H⁺).

Example 513: Synthesis of1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆):δ=12.64 (s, 1H), 8.98 (s, 1H), 8.25-8.22 (m,1H), 7.69-7.66 (m, 2H), 7.52 (br s, 2H), 7.34 (d, J=8.8 Hz, 2H),7.24-7.16 (m, 3H), 7.03 (d, J=8.8 Hz, 2H), 6.84 (d, J=7.2 Hz, 1H), 6.55(d, J=5.6 Hz, 1H), 6.51 (s, 1H), 4.15 (d, J=6.0 Hz, 2H), 2.18 (s, 3H).MS: m/z 446.8 (M+H⁺).

Example 514: Synthesis of1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.21 (s, 1H), 8.51-8.50 (m, 2H), 8.18 (d,J=1.6 Hz, 1H), 7.69-7.64 (m, 2H), 7.36 (d, J=9.2 Hz, 2H), 7.28 (d, J=5.6Hz, 2H), 7.23 (t, J=5.6 Hz, 1H), 7.07 (d, J=9.2 Hz, 4H), 6.91 (t, J=6.0Hz, 1H), 6.85 (d, J=8.0 Hz, 2H), 4.32 (d, J=6.0 Hz, 2H), 1.98 (s, 3H).MS: m/z 458.1 (M+H⁺).

Example 515: Synthesis of1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.1H NMR (400 MHz, DMSO-d6): δ=12.66 (s, 1H), 8.91 (s, 1H), 8.21-8.19 (m,1H), 7.69-7.64 (m, 2H), 7.54 (br s, 2H), 7.33 (d, J=5.2 Hz, 2H),7.24-7.21 (m, 1H), 7.09-7.05 (m, 4H), 6.85 (d, J=8.0 Hz, 2H), 6.51 (t,J=5.2 Hz, 1H), 4.15 (d, J=5.2 Hz, 2H), 2.36 (s, 3H). MS: m/z 466.8(M+H⁺).

Example 516: Synthesis of1-[4-(2′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆):δ=9.25 (s, 1H), 8.51-8.50 (m, 2H), 8.26-8.24(m, 1H), 7.74-7.71 (m, 2H), 7.43-7.40 (m, 3H), 7.36-7.25 (m, 5H),7.13-7.08 (m, 3H), 6.93 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS:m/z 477.7 (M+H⁺).

Example 517: Synthesis of1-[4-(2′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (s, 1H), 9.39 (s, 1H), 8.26-8.24 (m,1H), 7.75-7.71 (m, 2H), 7.53 (s, 2H), 7.44-7.40 (m, 3H), 7.36-7.31 (m,2H), 7.27-7.24 (m, 1H), 7.09 (d, J=8.8 Hz, 3H), 6.80 (t, J=5.2 Hz, 1H),4.15 (d, J=5.2 Hz, 2H). MS: m/z 466.7 (M+H⁺).

Example 518: Synthesis of1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepare using genera procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆):δ=9.26 (s, 1H), 8.51-8.49 (m, 2H), 8.24-8.22(m, 1H), 7.73-7.70 (m, 2H), 7.42 (d, J=8.8 Hz, 3H), 7.35-7.27 (m, 4H),7.11 (d, J=8.4 Hz, 2H), 7.00-6.97 (m, 1H), 6.92 (t, J=6.0 Hz, 1H), 6.84(t, J=2.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS: m/z 477.7 (M+H⁺).

Example 519: Synthesis of1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆):δ=12.72 (s, 1H), 10.05 (s, 1H), 8.23-8.20 (m,1H), 7.73-7.70 (m, 2H), 7.44-7.42 (m, 5H), 7.34-7.28 (m, 2H), 7.25 (t,J=5.2 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 6.96-6.92 (m, 2H), 4.10 (d, J=5.2Hz, 2H). MS: m/z 466.7 (M+H⁺).

Example 520: Synthesis of1-[4-(4′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.25 (s, 1H), 8.51-8.49 (m, 2H), 8.21-8.19(m, 2H), 7.72-7.68 (m, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz,2H), 7.29-7.28 (m, 3H), 7.13 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H),4.33 (d, J=5.6 Hz, 2H). MS: m/z 477.7 (M+H⁺).

Example 521: Synthesis of1-[4-(4′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.69 (s, 1H), 9.73 (s, 1H), 8.19 (d, J=6.4Hz, 1H), 7.73-7.67 (m, 2H), 7.53 (br s, 2H), 7.40 (d, J=8.4 Hz, 2H),7.35 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H),7.00 (d, J=8.4 Hz, 3H), 4.15 (d, J=5.2 Hz, 2H). MS: m/z 467.0 (M+H⁺).

Example 522: Synthesis of1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.20 (s, 1H), 8.50 (dd, J=4.8, 2.0 Hz, 2H),8.24-8.22 (m, 1H), 7.66-7.62 (m, 2H), 7.37-7.32 (m, 3H), 7.27 (d, J=6.0Hz, 2H), 7.19-7.17 (m, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.92-6.89 (m, 3H),6.79 (d, J=8.4 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.29 (s, 3H). MS: m/z473.8 (M+H⁺).

Example 523: Synthesis of1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.58 (s, 1H), 9.07 (s, 1H), 8.29-8.27 (m,1H), 7.70-7.67 (m, 2H), 7.58 (s, 2H), 7.41-7.37 (m, 3H), 7.23 (dd,J=5.6, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.98-6.96 (m, 2H), 6.84 (d,J=8.4 Hz, 1H), 6.63-6.61 (m, 1H), 4.19 (d, J=5.6 Hz, 2H), 3.3 (s, 3H).MS: m/z 463.1 (M+H⁺).

Example 524: Synthesis of1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.21 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),8.22 (d, J=7.2 Hz, 1H), 7.70-7.67 (m, 2H), 7.36 (d, J=9.2 Hz, 2H),7.29-7.25 (m, 3H), 7.19 (t, J=8.0 Hz, 1H), 7.07 (d, J=9.2 Hz, 2H),6.91-6.89 (m, 2H), 6.59 (d, J=7.6 Hz, 1H), 6.36 (t, J=2.0 Hz, 1H), 4.33(d, J=6.0 Hz, 2H), 3.62 (s, 3H). MS: m/z 474.1 (M+H⁺).

Example 525: Synthesis of1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.57 (s, 1H), 8.91 (s, 1H), 8.23-8.21 (m,1H), 7.70-7.67 (m, 2H), 7.53 (d, J=2.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H),7.27-7.25 (m, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.05 (d, J=9.2 Hz, 2H),6.92-6.89 (m, 1H), 6.59-6.51 (m, 2H), 6.37-6.36 (m, 1H), 4.15 (d, J=5.2Hz, 2H), 3.62 (s, 3H). MS: m/z 462.8 (M+H⁺).

Example 526: Synthesis of1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.20 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),8.20 (dd, J=7.6, 1.6 Hz, 1H), 7.69-7.64 (m, 2H), 7.36 (d, J=9.2 Hz, 2H),7.28 (d, J=6.0 Hz, 2H), 7.23 (dd, J=8.8, 1.6 Hz, 1H), 7.06 (d, J=8.4 Hz,2H), 6.90-6.87 (m, 3H), 6.83-6.81 (m, 2H), 4.32 (d, J=6.0 Hz, 2H), 3.79(s, 3H). MS: m/z 474.1 (M+H⁺).

Example 527: Synthesis of1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (s, 1H), 8.93 (s, 1H), 8.22-8.19 (m,1H), 7.68-7.63 (m, 4H), 7.33 (d, J=9.2 Hz, 2H), 7.24-7.22 (m, 1H), 7.05(d, J=8.8 Hz, 2H), 6.88 (dd, J=6.8, 2.4 Hz, 2H), 6.83-6.81 (m, 2H), 6.51(s, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). MS: m/z 462.8 (M+H⁺).

Example 528: Synthesis of1-(4-((3′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 1-bromo-2-((4-nitrophenyl)sulfonyl)benzene (400mg, 1.16 mmol) in dioxane/H₂O. (60 mL) (v/v, 5:1) was added(3-cyanophenyl)boronic acid (204 mg, 1.40 mmol), Pd(dppf)Cl₂ (84 mg,0.12 mmol) and potassium carbonate (480 mg, 3.48 mmol). After stirred at80° C. overnight under Ar balloon atmosphere, the reaction was filtratedand the filtrate was concentrated in vacuum to give a crude productwhich was purified by silica gel column (PE/EA=3/1) to give2′-((4-nitrophenyl)sulfonyl)-[1,1′-biphenyl]-3-carbonitrile (300 mg,71%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.39-8.37 (m, 1H),8.22 (d, J=8.8 Hz, 2H), 7.86-7.81 (m, 3H), 7.52-7.47 (m, 3H), 7.40-7.38(m, 1H), 7.31-7.29 (m, 1H), 7.22 (s, 1H).

Step 2: To a solution of2′-((4-nitrophenyl)sulfonyl)-[1,1′-biphenyl]-3-carbonitrile (300 mg,0.82 mmol) in EtOH/H₂O (60 mL) (v/v, 5:1) was added iron (230 mg, 4.1mmol) and NH₄Cl (217 mg, 4.1 mmol). The reaction mixture was stirred at80° C. overnight. The reaction was monitored by LCMS and TLC. Aftercompletion, the reaction mixture was filtrated and the cake was washedwith EtOH. Then the combined solvent was concentrated in vacuum to givea crude product which was purified by silica gel column (PE/EA=4/1) togive 2′-((4-aminophenyl)sulfonyl)-[1,1′-biphenyl]-3-carbonitrile (250mg, 91%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆):δ=8.17-8.15 (m,1H), 7.84 (d, J=7.6 Hz, 1H), 7.72-7.68 (m, 2H), 7.54 (t, J=8.0 Hz, 1H),7.40 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 7.29-7.27 (m, 1H), 6.85 (d, J=8.8Hz, 2H), 6.41 (d, J=8.8 Hz, 2H), 6.16 (s, 2H).

Step 3: To a solution of2′-((4-aminophenyl)sulfonyl)-[1,1′-biphenyl]-3-carbonitrile (250 mg,0.75 mmol) in DCM (20 mL) was added phenyl chloroformate (312 mg, 2.0mmol) and TEA (0.5 mL). The mixture was stirred at room temperatureovernight. The reaction was monitored by TLC and LCMS. After completion,the mixture was concentrated in vacuum to give a crude product which waspurified by a silica gel column (PE/EA=3/1) to afford phenyl(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (300 mg,88%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=10.73 (s, 1H),8.29-8.26 (m, 1H), 7.83-7.81 (m, 1H), 7.78-7.75 (m, 2H), 7.52-7.50 (m,1H), 7.46-7.43 (m, 1H), 7.39-7.37 (m, 3H), 7.34-7.30 (m, 1H), 7.28-7.22(m, 2H), 7.19 (s, 2H), 7.17 (s, 3H).

Step 4: To a solution of phenyl(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (100 mg,0.22 mmol) in ACN (20 mL) was added Pyridin-4-ylmethanamine (31 mg, 0.25mmol) and TEA (0.5 mL). Then the mixture was stirred at 80° C.overnight. The reaction was monitored by TLC and LCMS. After completion,the mixture was concentrated in vacuum to give a crude product which waspurified by pre-HPLC to afford1-(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea(60.5 mg, 59%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.29 (s,1H), 8.50 (d, J=6.0 Hz, 2H), 8.25-8.23 (m, 1H), 7.84 (s, 1H), 7.76-7.73(m, 2H), 7.53 (t, J=8.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.37 (d, J=4.8Hz, 1H), 7.32 (d, J=2.0 Hz, 3H), 7.29 (d, J=5.2 Hz, 1H), 7.08 (d, J=8.8Hz, 2H), 6.92 (d, J=5.6 Hz, 2H), 4.33 (d, J=5.6 Hz, 2H). MS: m/z 468.7(M+H⁺).

Example 529: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea

To a solution of(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (150 mg,0.33 mmol) in ACN (20 mL) was added (1H-pyrazol-4-yl)methanamine (35 mg,0.36 mmol) and TEA (0.5 mL). The mixture was stirred at 80° C.overnight. The reaction was monitored by TLC and LCMS. After completion,the mixture was concentrated in vacuum to give a residue which waspurified by prep-TLC (DCM/MeOH=10/1) to afford(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)carbamate (30.1 mg,20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=12.66 (s, 1H), 8.98(s, 1H), 8.23 (d, J=5.6 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.74 (s, 2H),7.62-7.50 (m, 2H), 7.41-7.28 (m, 6H), 7.08 (d, J=8.0 Hz, 2H), 6.52 (s,1H), 4.15 (d, J=5.6 Hz, 2H). MS: m/z 457.8 (M+H⁺).

Example 530: Synthesis of1-[4-(4′-Cyano-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.36 (s, 1H), 8.54 (d, J=3.6 Hz, 2H), 8.21(d, J=6.4 Hz, 1H), 7.77-7.71 (m, 4H), 7.42 (d, J=8.4 Hz, 2H), 7.35 (d,J=4.4 Hz, 2H), 7.29 (d, J=6.4 Hz, 1H), 7.20-7.11 (m, 4H), 7.04-6.98 (m,1H), 4.36 (d, J=6.0 Hz, 2H). MS: m/z 468.8 (M+H⁺).

Example 531: Synthesis of1-[4-(4′-Cyano-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆):δ=12.63 (s, 1H), 9.00 (s, 1H), 8.23-8.21 (m,1H), 7.77-7.72 (m, 4H), 7.53 (br s, 2H), 7.39 (d, J=8.8 Hz, 2H),7.30-7.28 (m, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.55(s, 1H), 4.15 (d, J=5.6 Hz, 2H). MS: m/z 457.8 (M+H⁺).

Example 532: Synthesis of1-[4-(2-Pyridin-3-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CD₃OD): δ=8.48-8.44 (m, 3H), 8.34 (d, J=6.8 Hz, 1H),8.06 (s, 1H), 7.68 (s, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.37-7.36 (m, 5H),7.25 (d, J=6.4 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 4.43 (s, 2H). MS: m/z445.1 (M+H)⁺.

Example 533: Synthesis of1-{4-[2-(6-Methoxy-pyridin-3-yl)-benzenesulfonyl]-phenyl}-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.20 (s, 1H), 8.50 (dd, J=4.4, 1.6 Hz, 2H),8.23 (dd, J=7.6, 1.6 Hz, 1H), 7.75-7.68 (m, 2H), 7.62 (d, J=2.0 Hz, 1H),7.41-7.36 (m, 3H), 7.32-7.27 (m, 3H), 7.09 (d, J=9.2 Hz, 2H), 6.93-6.77(m, 1H), 6.75 (d, J=0.8 Hz, 1H), 4.32 (d, J=6.0 Hz, 2H), 3.87 (s, 3H).MS: m/z 474.8 (M+H⁺).

Example 534: Synthesis of1-{4-[2-(6-Methoxy-pyridin-3-yl)-benzenesulfonyl]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (s, 1H), 8.94 (s, 1H), 8.23 (dd,J=7.6, 1.6 Hz, 1H), 7.75-7.67 (m, 2H), 7.63 (d, J=2.0 Hz, 1H), 7.53 (s,2H), 7.39-7.35 (m, 3H), 7.31-7.29 (m, 1H), 7.08 (d, J=4.8 Hz, 2H),6.77-6.75 (m, 1H), 6.52 (t, J=5.2 Hz, 1H), 4.14 (d, J=5.2 Hz, 2H), 3.88(s, 3H). MS: m/z 463.8 (M+H⁺).

Example 535: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-3-yl-benzenesulfonyl)-phenyl]-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CD₃OD): δ=8.50-8.49 (m, 1H), 8.38-8.36 (m, 1H), 8.07(d, J=1.2 Hz, 1H), 7.74-7.71 (m, 2H), 7.58-7.52 (m, 3H), 7.39-7.28 (m,4H), 7.09 (d, J=9.2 Hz, 2H), 4.28 (s, 2H). MS: m/z 433.8 (M+H)⁺.

Example 536: Synthesis of1-[4-(2-Pyridin-4-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.76 (s, 1H), 8.84 (d, J=6.4 Hz, 2H), 8.73(d, J=6.8 Hz, 2H), 8.20-8.18 (m, 1H), 7.90 (d, J=6.8 Hz, 2H), 7.81-7.77(m, 2H), 7.51-7.46 (m, 5H), 7.38-7.36 (m, 1H), 7.30 (d, J=9.2 Hz, 2H),4.57 (s, 2H). MS: m/z 445.1 (M+H)⁺.

Example 537: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-urea

Step 1: To a solution of 4-[(2-bromophenyl)sulfonyl]-1-nitrobenzene (400mg, 1.17 mmol) in a mixture of dioxane (10 mL) and H₂O (1 mL) was addedK₂CO₃ (324 mg, 2.34 mmol), Pd(dppf)Cl₂ (103 mg, 0.12 mmol) andpyridine-4-boronic acid (173 mg, 1.4 mmol). Then the mixture was stirredat 80° C. for 6 hrs. This reaction was monitored by LC-MS. The reactionmixture was then diluted with H₂O (10 mL) and extracted with EA (10mL×3). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and evaporated in vacuum to give the crude product which wasused to the next step without further purification.

Step 2: To a solution of 4-[2-(4-nitro-benzenesulfonyl)-phenyl]-pyridine(486 mg, 1.43 mmol) in a mixture of EtOH (10 mL) and H₂O (1 mL) wasadded iron (320 mg, 5.6 mmol) and NH₄Cl (306 mg, 5.6 mmol). Then themixture was stirred at 80° C. overnight. This reaction was monitored byTLC (PE/EA=1/4). The reaction mixture was then diluted with H₂O (10 mL)and extracted with EA (10 mL×3). The combined organic layer was driedover anhydrous Na₂SO₄, and evaporated in vacuum. The residue waspurified by silica gel chromatography column (PE/EA=1/4) to give4-(2-pyridin-4-yl-benzenesulfonyl)-phenylamine (324 mg, 73.1%) as yellowoil. ¹H NMR (400 MHz, DMSO-d₆): δ=8.51-8.50 (m, 2H), 7.96 (s, 2H),7.06-7.04 (m, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.41 (d, J=8.8 Hz, 2H), 6.15(s, 2H).

Step 3: To a solution of 4-(2-pyridin-4-yl-benzenesulfonyl)-phenylamine(324 mg, 1.05 mmol) in DCM (10 mL) was added phenyl chloroformate (196.3mg, 1.26 mmol) and TEA (211.5 mg, 2.1 mmol). Then the mixture wasstirred at room temperature overnight. This reaction was monitored byLC-MS. The solvent was removed by vacuo. The residue was purificated bysilica gel column chromatography (PE/EA=4/1) to give[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(364 mg, 81%) as yellow oil which was used to the next step withoutfurther purification.

Step 4: To a solution of[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-carbamic acid phenyl ester(100 mg, 0.23 mmol) in ACN (10 mL) was added(1H-pyrazol-3-yl)methanamine (27.1 mg, 0.28 mmol) and TEA (47.1 mg, 0.47mmol). Then the mixture was stirred at 80° C. for 2 hrs. This reactionwas monitored by LCMS. The reaction mixture was then diluted with H₂O(10 mL) and extracted with EA (10 mL×3). The combined organic layer wasdried over anhydrous Na₂SO₄, and evaporated in vacuum. The residue waspurified by prep-HPLC to give1-(1H-pyrazol-4-ylmethyl)-3-[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-urea(21.3 mg, 21%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.43-8.41(m, 2H), 8.34-8.32 (m, 1H), 7.72-7.69 (m, 2H), 7.58 (s, 2H), 7.36-7.34(m, 2H), 7.27-7.25 (m, 1H), 7.18-7.15 (m, 2H), 7.08-7.07 (m, 2H), 4.28(s, 2H). MS: m/z 433.8 (M+H)⁺.

Example 538: Synthesis of1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 4-(benzo[d]thiazol-2-yl)aniline (226 mg, 1.0mmol) in DCM (20 mL) was added phenyl carbonchloridate (235 mg, 1.50mmol) and followed by TEA (304 mg, 3.0 mmol). The resulting mixture wasstirred at room temperature for 1 hr. Then the mixture was concentratedin vacuum. The residue was purified by silica gel column (PE/EA=10/1 to3/1) to afford phenyl (4-(benzo[d]thiazol-2-yl)phenyl)carbamate (326 mg,yield 94%) as a white solid.

Step 2: To a solution of phenyl(4-(benzo[d]thiazol-2-yl)phenyl)carbamate (100 mg, 0.29 mmol) in ACN (20mL) was added c-pyridin-4-yl-methylamine (37 mg, 0.35 mmol) and followedby TEA (88 mg, 0.87 mmol). The resulting mixture was stirred at 80° C.for 2 hrs. Then the mixture was concentrated in vacuum. The residue waspurified by a prep-HPLC with NH₄HCO₃ as additive to afford1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea (52.4 mg,yield 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.16 (br s,1H), 8.52 (d, J=6.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 1H), 8.03-7.94 (m, 3H),7.62 (d, J=8.8 Hz, 2H), 7.52 (t, J=8.4 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H),7.31 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.0 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H).MS: m/z 361.0 (M+H⁺).

Example 539: Synthesis of1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared as described in example phenyl(4-(benzo[d]thiazol-2-yl)phenyl)carbamate. ¹H NMR (400 MHz, DMSO-d₆):δ=9.02 (br s, 1H), 8.31 (s, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.04-7.93 (m,3H), 7.61 (d, J=8.8 Hz, 2H), 7.52 (t, J=7.2 Hz, 1H), 7.42 (t, J=7.2 Hz,1H), 7.04 (s, 1H), 6.80 (t, J=6.0 Hz, 1H), 4.40 (d, J=5.6 Hz, 2H). MS:m/z 350.9 (M+H⁺).

Example 540: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-yl)phenyl)urea

The title compound was prepared as described in example phenyl(4-(benzo[d]thiazol-2-yl)phenyl)carbamate. ¹H NMR (400 MHz, DMSO-d₆):δ=12.67 (br s, 1H), 8.99 (s, 1H), 8.10 (d, J=8.0 Hz, 1H), 8.04-7.90 (m,3H), 7.74-7.46 (m, 5H), 7.42 (t, J=7.6 Hz, 1H), 6.58 (t, J=4.8 Hz, 1H),4.18 (d, J=4.4 Hz, 2H). MS: m/z 350.0 (M+H⁺).

Example 541: Synthesis of1-(4-(5-Phenylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1 to Step 2: To a solution of 2-phenylacetaldehyde (3.6 g, 30.0mmol) in dioxane (40 mL) was added Br₂ (5.27 g, 33.0 mmol) dropwise at0° C. over 10 min. The resulting mixture was stirred at 0° C. for 10 minand allowed to warm to room temperature for 10 min. The reaction mixturewas concentrated in vacuum. The residue was dissolved in EtOH (60 mL)and 4-nitrobenzothioamide (4.35 g, 23.9 mmol) was added. The resultingmixture was stirred at 80° C. overnight. The mixture was concentrated invacuum. The residue was purified by silica gel column (PE/EA=10/1 to3/1) to afford 2-(4-nitrophenyl)-5-phenylthiazole (3.76 g, yield 44%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.32 (d, J=9.2 Hz, 2H),8.18-8.19 (m, 3H), 7.63 (d, J=8.4 Hz, 2H), 7.46 (t, J=7.2 Hz, 2H), 7.39(t, J=7.2 Hz, 1H).

Step 3: To a solution of 2-(4-nitrophenyl)-5-phenylthiazole (3.76 g,13.32) mmol) in MeOH (60 mL) was added Pd/C (376 mg, 10% wt). Theresulting mixture was stirred at room temperature under H₂ (50 psi)atmosphere overnight. Then Pd/C was removed by filtration. The filtratewas concentrated in vacuum. The residue was purified by reverse-phasecolumn (ACN in H₂O from 10% to 80%, 60 mins) to afford4-(5-phenylthiazol-2-yl)aniline (762 mg, yield 16%) as a pale-yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.12 (br s, 1H), 7.65 (t, J=8.0 Hz,4H), 7.44 (d, J=7.6 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 6.64 (t, J=8.4 Hz,2H), 5.72 (br s, 2H).

Step 4: To a solution of 4-(5-phenylthiazol-2-yl)aniline (300 mg, 1.19mmol) in dry DCM (30 mL) was added phenyl carbonochloridate (410 mg,2.62 mmol) and followed by TEA (361 mg, 3.57 mmol). The resultingmixture was stirred at room temperature for 1 hour. Then the mixture wasconcentrated in vacuum. The residue was purified by silica gel column(PE/EA=100/1 to 10/1) to afford phenyl(4-(5-phenylthiazol-2-yl)phenyl)carbamate (445 mg, yield 76%) as a whitesolid.

Step 5:

To a solution of phenyl (4-(5-phenylthiazol-2-yl)phenyl)carbamate (120mg, 0.24 mmol) in ACN (20 mL) was added pyridin-4-ylmethanamine (53 mg,0.48 mmol) and followed by TEA (74 mg, 0.72 mmol). The resulting mixturewas stirred at 80° C. overnight. Then the mixture was concentrated invacuum. The residue was purified by prep-HPLC with NH₄OH as additive toafford 1-(4-(5-phenylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea(38.7 mg, yield 41%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.05(br s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.24 (s, 1H), 7.85 (d, J=8.8 Hz,2H), 7.70 (d, J=7.6 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.46 (t, J=7.2 Hz,2H), 7.37 (t, J=7.6 Hz, 1H), 7.31 (d, J=5.6 Hz, 2H), 6.86 (t, J=6.0 Hz,1H), 4.35 (d, J=6.0 Hz, 2H). MS: m/z 387.0 (M+H⁺).

Example 542: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea

The title compound was prepared as described in example1-(4-(5-phenylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹H NMR(400 MHz, DMSO-d₆): δ=8.96 (br s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.85(d, J=8.8 Hz, 2H), 7.70 (d, J=7.6 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.46(t, J=7.6 Hz, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.77 (t, J=5.6Hz, 1H), 4.39 (d, J=5.2 Hz, 2H). MS: m/z 377.1 (M+H⁺).

Example 543: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea

The title compound was prepared as described in example1-(4-(5-phenylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹H NMR(400 MHz, DMSO-d₆): δ=12.58 (br s, 1H), 8.77 (s, 1H), 8.24 (s, 1H), 7.84(d, J=8.4 Hz, 2H), 7.70 (d, J=6.8 Hz, 2H), 7.63-7.51 (m, 4H), 7.46 (t,J=7.2 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 6.46 (t, J=5.6 Hz, 1H), 4.17 (d,J=5.2 Hz, 2H). MS: m/z 376.1 (M+H⁺).

Example 544: Synthesis of1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 3-phenylpropanal (500 mg, 3.7 mmol) in DCM (50mL) was added Br₂ (566 mg, 3.5 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 3 hrs. To the reaction mixture was addedsat.NaHCO₃ solution (10 mL) with stirring. The organic layer was washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel column (PE/EA=10/1) to give2-bromo-3-phenylpropanal (crude 1.1 g, yield quantitative) as yellowoil.

Step 2: To a solution of 2-bromo-3-phenylpropanal (1.1 g, 3.7 mmol) inEtOH (100 mL) was added thiourea (340 mg, 4.4 mmol). The reaction wasstirred at 80° C. for 6 hrs. The reaction mixture was cooled to roomtemperature and poured into sat.NaHCO₃ solution (15 mL). The aqueousphase was extracted with EA (20 mL). The organic layer was washed withbrine (15 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel column (PE/EA=1/1) to give5-benzylthiazol-2-amine (350 mg, yield 50%) as a yellow solid.

Step 3: To a solution of 5-benzylthiazol-2-amine (350 mg, 1.84 mmol) inACN (30 mL) was added CuBr₂ (821 mg, 3.68 mmol) and BuONO (431 mg, 3.68mmol). The reaction was stirred at 50° C. for 0.5 hrs. The reactionmixture was cooled to room temperature and poured into H₂O (15 mL). Theaqueous phase was extracted with EA (30 mL). The organic layer waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by silica gel column (PE/EA=4/1) to give5-benzyl-2-bromothiazole (300 mg, yield 64%) as yellow oil.

Step 4: To a solution of 5-benzyl-2-bromothiazole (300 mg, 1.19 mmol)and (4-nitrophenyl)boronic acid (400 mg, 2.37 mmol) in dioxane/H₂O (4/1,25 mL) was added Pd(dppf)Cl₂ (175 mg, 0.24 mmol) and K₂CO₃ (500 mg, 3.6mmol). The reaction was stirred at 90° C. overnight.

The reaction mixture was cooled to room temperature and poured into H₂O(10 mL). The aqueous phase was extracted with EA (20 mL). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel column (PE/EA=5/1)to give 5-benzyl-2-(4-nitrophenyl)thiazole (250 mg, yield 71%) as ayellow solid.

Step 5: To a solution of 5-benzyl-2-(4-nitrophenyl)thiazole (250 mg,0.84 mmol) in EtOH/H₂O (4/1, 25 mL) was added NH₄Cl (445 mg, 8.4 mmol)and Fe (330 mg, 6 mmol). The reaction was stirred at 90° C. overnight.The reaction mixture was cooled to room temperature and poured into H₂O(20 mL). The aqueous phase was extracted with EA (25 mL). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel column (PE/EA=2/1)to give 4-(5-benzylthiazol-2-yl)aniline (100 mg, yield 49%) as yellowoil.

Step 6: To a solution of 4-(5-benzylthiazol-2-yl)aniline (100 mg, 0.38mmol) and phenyl carbonochloridate (70 mg, 0.45 mmol) in DCM was addedTEA (120 mg, 1.14 mmol). The reaction was stirred at 0° C. for 1 hr. Theorganic layer was washed with brine (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by silica gel column(PE/EA=2/1) to give phenyl (4-(5-benzylthiazol-2-yl)phenyl)carbamate (80mg, yield 53%) as a white solid.

Step 7: To a solution of phenyl(4-(5-benzylthiazol-2-yl)phenyl)carbamate (40 mg, 0.1 mmol) andpyridin-4-ylmethanamine (14 mg, 0.12 mmol) in ACN was added TEA (31 mg,0.3 mmol). The reaction was stirred at 80° C. for 3 hrs. The reactionmixture was cooled to room temperature and poured into H₂O (20 mL). Theaqueous phase was extracted with EA (20 mL). The organic layer waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by prep-HPLC (NH₄HCO₃) to give1-(4-(5-benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea (18.6 mg,yield 50%) as a white solid. ¹H NMR (400 MHz, CDCl₃+CD₃OD): δ 8.50 (d,J=6.0 Hz, 2H), 7.77 (d, J=8.4 Hz, 2H), 7.71 (s, 1H), 7.51 (d, J=8.8 Hz,3H), 7.41 (d, J=5.6 Hz, 2H), 7.36-7.24 (m, 5H), 4.49 (s, 2H), 4.20 (s,2H). MS: m/z 401.0 (M+H⁺).

Example 545: Synthesis of1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(5-benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹H NMR(400 MHz, CDCl₃+CD₃OD): δ=7.97 (s, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.50(dd, J=6.4 Hz, 4H), 7.39-7.28 (m, 5H), 7.04 (s, 1H), 4.58 (s, 3H), 4.21(s, 2H).

MS: m/z 391.0 (M+H⁺).

Example 546: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-benzylthiazol-2-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(5-benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹H NMR(400 MHz, DMSO-d₆): δ=12.66 (s, 1H), 8.70 (s, 1H), 7.72 (d, J=8.8 Hz,2H), 7.62 (s, 2H), 7.48 (d, J=8.8 Hz, 3H), 7.35-7.23 (m, 5H), 6.44 (t,J=5.6 Hz, 1H), 4.19 (s, 2H), 4.16 (d, J=5.2 Hz, 2H). MS: m/z 390.0(M+H⁺).

Example 547: Synthesis of1-(4-Benzothiazol-4-yl-phenyl)-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-(4-benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea. ¹H NMR (400MHz, DMSO-d₆): δ=9.41 (s, 1H), 8.87 (s, 1H), 8.52-8.51 (m, 2H),8.13-8.10 (m, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.63-7.61 (m, 1H), 7.56-7.52(m, 3H), 7.31 (d, J=6.0 Hz, 2H), 6.80 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6Hz, 2H). MS: m/z 361.0 (M+H⁺).

Example 548: Synthesis of1-(4-Benzothiazol-4-yl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-(4-benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea. ¹H NMR (400MHz, DMSO-d₆): δ=12.60 (s, 1H), 9.41 (s, 1H), 8.58 (s, 1H), 8.12-8.11(m, 1H), 7.78-7.76 (m, 2H), 7.62-7.51 (m, 6H), 6.38 (s, 1H), 4.17 (s,2H). MS: m/z 350.1 (M+H⁺).

Example 549: Synthesis of1-(4-Benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea

Step 1: To a mixture of 4-bromo-benzothiazole (500 mg, 2.3 mmol),4-nitrophenylboronic acid (576 mg, 3.45 mmol) and K₂CO₃ (952.2 mg, 6.9mmol) in dioxane/H₂O (20 mL/10 mL) was added Pd(PPh₃)₄ (132 mg, 0.115mmol). The mixture was stirred at 95° C. under N₂ overnight. The mixturewas concentrated. The residue was purified with flash to give4-(4-nitro-phenyl)-benzothiazole (288 mg, yield 49%) as a yellow solid.¹H NMR (300 MHz, DMSO-d₆) δ=9.51 (s, 1H), 8.38-8.30 (m, 3H), 8.17 (d,J=8.7 Hz, 2H), 7.79 (d, J=7.5 Hz, 1H), 7.651 (t, J=7.5 Hz, 1H). MS: m/z257.0 (M+H⁺).

Step 2: To a mixture of 4-(4-nitro-phenyl)-benzothiazole (288 mg, 1.125mmol), Fe (75.6 mg, 1.35 mmol) and NH₄Cl (135 mg, 2.25 mol) in EtOH/H₂O(10 mL/4 mL) was stirred at 80° C. for 1 hr. The reaction was completeddetected by LC-MS. The mixture was filtered and extracted with EA. Theorganic layer was concentrated to give the crude4-benzothiazol-4-yl-phenylamine (151 mg, yield 59%) as a white solid.MS: m/z 227.0 (M+H⁺).

Step 3: To a mixture of 4-benzothiazol-4-yl-phenylamine (131 mg, 0.58mmol) and pyridine (92.8 mg, 0.16 mmol) in DCM (5 mL) was added phenylchloroformate (108 mg, 0.696 mmol) at 0° C. dropwise. The reactionmixture was allowed to warm to room temperature for 1 hr. The reactionwas completed detected by LC-MS. The organic layer was washed with brine(5 mL), dried over Na₂SO₄, filtered and concentrated to the crude give(4-benzothiazol-4-yl-phenyl)-carbamic acid phenyl ester (150 mg, yield75%) as a yellow solid. MS: m/z 347.0 (M+H⁺).

Step 4: To a mixture of (4-benzothiazol-4-yl-phenyl)-carbamic acidphenyl ester (51 mg, 0.15 mmol) and c-oxazol-5-yl-methylamine (25 mg,0.19 mmol) in ACN (5 mL) was added TEA (30.3 mg, 0.3 mmol). The mixturewas stirred at 80° C. for 4 hrs. The reaction was completed detected byLC-MS. The mixture was washed with H₂O, filtered and purified byPrep-HPLC to give1-(4-benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea (21.7 mg, yield41%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.40 (s, 1H), 8.73(s, 1H), 8.29 (s, 1H), 8.12-8.09 (m, 1H), 7.77 (d, J=8.8 Hz, 2H),7.61-7.60 (m, 1H), 7.55-7.50 (m, 3H), 7.02 (s, 1H), 6.68 (t, J=5.6 Hz,1H), 4.39 (d, J=6.0 Hz, 2H). MS: m/z 351.1 (M+H⁺).

Example 550: Synthesis of1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1H-benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹H NMR(400 MHz, DMSO-d₆): δ=12.5 (s, 1H), 8.85-8.84 (m, 1H), 8.52 (d, J=5.6Hz, 2H), 8.244 (s, 1H), 8.05 (d, J=5.6 Hz, 1H), 7.57-7.36 (m, 5H), 7.32(d, J=5.2 Hz, 2H), 7.26 (t, J=6.8 Hz, 1H), 6.82-6.81 (m, 1H), 4.36 (d,J=5.6 Hz, 1H). MS: m/z 344.1 (M+H⁺).

Example 551: Synthesis of1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(h-benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea. ¹H NMR(400 MHz, DMSO-d₆): δ=12.62 (s, 2H), 8.56 (s, 1H), 8.25 (s, 1H), 7.88(s, 2H), 7.56-7.50 (m, 5H), 7.33 (d, J=7.2 Hz, 1H), 7.26 (t, J=7.6 Hz,1H), 6.37 (t, J=5.6 Hz, 1H), 4.18 (d, J=5.2 Hz, 2H). MS: m/z 333.1(M+H⁺).

Example 552: Synthesis of1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

Step 1: To a mixture of 4-bromo-1H-benzoimidazole (500 mg, 2.5 mmol) andTEA (757.5 mg, 7.5 mmol) in THF (10 mL) was added Boc₂O (834 mg, 3.8mmol) and DMAP (151 mg, 1.25 mmol). The mixture was stirred at roomtemperature overnight. The mixture was concentrated and purified bysilia gel chromatography (PE/EA=5/1) to give4-bromo-benzoimidazole-1-carboxylic acid tert-butyl ester (700 mg, yield95%) as yellow liquid. ¹H NMR (300 MHz, CDCl₃): δ=8.48 (s, 1H), 7.97 (d,J=8.1 Hz, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.30-7.25 (m, 1H), 1.26 (t, J=7.2Hz, 9H). MS: m/z 296.0 (M+H⁺).

Step 2: To a mixture of 4-bromo-benzoimidazole-1-carboxylic acidtert-butyl ester (625 mg, 2.1 mmol), 4-nitrophenylboronic acid (423 mg,2.5 mmol) and K₂CO₃ (869 mg, 6.3 mmol) in dioxane/H₂O (20 mL/10 mL), wasadded Pd(PPh₃)₄ (111.5 mg, 0.21 mmol). The mixture was stirred at 95° C.under N₂ overnight. The mixture was concentrated and purified by flashto give 4-(4-nitro-phenyl)-benzoimidazole-1-carboxylic acid tert-butylester (383 mg, yield 44%) as a yellow solid. MS: m/z 240.0 (M−100+H1).

Step 3: To a mixture of 4-(4-nitro-phenyl)-benzoimidazole-1-carboxylicacid tert-butyl ester (333 mg, 1.12 mmol) in MeOH/THF (5 mL/1 mL) wasadded Pd/C (33 mg, wet 10%). The reaction mixture was stirred at roomtemperature under H₂ (1 atm) overnight. Pd/C was filtered and thefiltrate was concentrated in vacuum to give the crude4-(4-amino-phenyl)-benzoimidazole-1-carboxylic acid tert-butyl ester(300 mg, yield 86%) as a yellow solid. MS: m/z 310.0 (M+H⁺).

Step 4: To a mixture of 4-(4-amino-phenyl)-benzoimidazole-1-carboxylicacid tert-butyl ester (300 mg, 0.96 mmol) and pyridine (153 mg, 1.92mmol) in DCM (5 mL) was added phenyl chloroformate (165 mg, 1.06 mmol)at 0° C. dropwise. The reaction mixture was allowed to warm to roomtemperature for 2 hrs. The reaction was completed detected by LC-MS. Theorganic layer was washed with brine (5 mL), dried over Na₂SO₄ filteredand concentrated to give the crude4-(4-phenoxycarbonylamino-phenyl)-benzoimidazole-1-carboxylic acidtert-butyl ester (160 mg, yield 39%) as a yellow solid. MS: m/z 330.0(M−100+H1).

Step 5: To a mixture of4-(4-phenoxycarbonylamino-phenyl)-benzoimidazole-1-carboxylic acidtert-butyl ester (40 mg, 0.093 mmol) and C-Oxazol-5-yl-methylamine (15mg, 0.011 mmol) in ACN (5 mL) was added TEA (28.1 mg, 0.27 mmol). Themixture was stirred at room temperature overnight. The reaction wascompleted detected by LC-MS. The mixture was washed with H₂O andfiltered to give the crude4-[4-(3-Oxazol-5-ylmethyl-ureido)-phenyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (30 mg, yield 49%) as a brown solid. MS: m/z 334.0(M−100+H⁺).

Step 6: A mixture of4-[4-(3-oxazol-5-ylmethyl-ureido)-phenyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (30 mg, 69 mmol) in MeOH/HCl (2 mL) was stirred atroom temperature overnight. The reaction was completed detected byLC-MS. The mixture was purified with prep-HPLC to give1-[4-(1H-benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea (3 mg,yield 13%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=12.53 (s, 1H),8.69 (s, 1H), 8.3 (s, 1H), 8.24 (s, 1H), 8.05 (d, J=7.6 Hz, 1H),7.55-7.45 (m, 4H), 7.37 (d, J=7.2 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.03(s, 1H), 6.66 (s, 1H), 4.40 (d, J=5.6 Hz, 2H). MS: m/z 334.1 (M+H⁺).

Example 553: Synthesis of1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 2-bromo-1-phenylethanone (1.99 g, 10.0 mmol) inEtOH (40 mL) was added thiourea (0.84 g, 11.0 mmol). The resultingmixture was stirred at 80° C. overnight.

Then the mixture was concentrated in vacuum. The residue was purified bysilica gel column (DCM/MeOH=60/1) to afford 4-phenylthiazol-2-amine(1.56 g, yield 89%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.27(br s, 2H), 7.75 (d, J=7.2 Hz, 2H), 7.50-7.42 (m, 2H), 7.41-7.35 (m,1H), 7.17 (s, 1H).

Step 2: To a solution of 4-phenylthiazol-2-amine (1.38 g, 7.83 mmol) and1-bromo-4-nitrobenzene (1.90 g, 9.40 mmol) in toluene (40 mL) was addedPd₂(dba)₃ (358 mg, 0.39 mmol), BINAP (244 mg, 0.39 mmol) and t-BuOK(1.76 g, 15.6 mmol). The resulting mixture was stirred at 80° C. underN₂ atmosphere overnight. Then the mixture was filtered and concentratedin vacuum. The residue was purified by silica gel column (PE/EA=100/1 to30/1) to afford N-(4-nitrophenyl)-4-phenylthiazol-2-amine (1.08 g, yield46%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=11.09 (br s, 1H),8.28 (d, J=9.2 Hz, 2H), 8.02-7.89 (m, 4H), 7.56 (s, 1H), 7.46 (t, J=7.6Hz, 2H), 7.35 (t, J=7.2 Hz, 1H).

Step 3: To a solution of N-(4-nitrophenyl)-4-phenylthiazol-2-amine (1.08g, 3.63 mmol) in MeOH (30 mL) was added Pd/C (216 mg, 20% wt). Theresulting mixture was stirred at room temperature under H₂ atmospherefor 2 hours. Then Pd/C was filtered and the filtrate was concentrated invacuum. The residue was purified by reverse-phase column (ACN in H₂O,5-95%, 40 mins) to afford N¹-(4-phenylthiazol-2-yl)benzene-1,4-diamine(680 mg, yield 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.68(br s, 1H), 7.87 (d, J=7.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.33-7.23(m, 3H), 7.15 (s, 1H), 6.57 (d, J=8.8 Hz, 2H), 4.85 (br s, 2H).

Step 4: To a solution of N¹-(4-phenylthiazol-2-yl)benzene-1,4-diamine(680 mg, 2.54 mmol) in dry DCM (20 mL) was added phenylcarbonochloridate (478 mg, 3.05 mmol) and followed by TEA (771 mg, 7.62mmol). The resulting mixture was stirred at room temperature for 1 hour.Then the mixture was concentrated in vacuum. The residue was purified bysilica gel column (PE/EA=10/1 to 4/1) to afford phenyl(4-((4-phenylthiazol-2-yl)amino)phenyl)carbamate (476 mg, yield 48%) asa white solid.

Step 5: To a solution of phenyl(4-((4-phenylthiazol-2-yl)amino)phenyl)carbamate (120 mg, 0.31 mmol) inACN (20 mL) was added pyridin-4-ylmethanamine (40.4 mg, 0.37 mmol) andfollowed by TEA (94.0 mg, 0.93 mmol). The resulting mixture was stirredat 80° C. for 3 hours. Then the mixture was concentrated in vacuum. Theresidue was purified by prep-HPLC with NH₄OH as additive to afford1-(4-((4-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea(13.0 mg, yield 10%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆):δ=10.09 (br s, 1H), 8.62 (br s, 1H), 8.52 (dd, J=4.8, 1.6 Hz, 2H), 7.91(d, J=7.2 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.42 (t, J=7.2 Hz, 2H), 7.39(t, J=8.8 Hz, 2H), 7.34-7.29 (m, 3H), 7.28 (s, 1H), 6.72 (t, J=6.4 Hz,1H), 4.34 (d, J=6.0 Hz, 2H). MS: m/z 402.0 (M+H⁺).

Example 554: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea

The title compound was prepared as described in example1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.58 (br s, 1H), 10.06 (br s, 1H), 8.31 (brs, 1H), 7.91 (d, J=7.2 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.56-7.47 (m,2H), 7.42 (t, J=7.6 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.28 (d, J=7.2 Hz,1H), 7.26 (s, 1H), 6.27 (t, J=5.6 Hz, 1H), 4.14 (d, J=5.6 Hz, 2H). MS:m/z 391.0 (M+H⁺).

Example 555: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea

The title compound was prepared as described in example1-(4-((4-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=10.12 (br s, 1H), 8.62 (br s, 1H), 8.29 (s,1H), 7.91 (d, J=7.6 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.42 (t, J=7.6 Hz,2H), 7.37 (d, J=8.8 Hz, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.27 (s, 1H), 7.01(s, 1H), 6.67 (t, J=6.0 Hz, 1H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 392.0(M+H⁺).

Example 556: Synthesis of 1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)urea

The title compound was prepared as described in example1-(4-((4-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=10.07 (br s, 1H), 8.46 (br s, 1H), 7.91 (d,J=7.6 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.36 (d,J=9.2 Hz, 2H), 7.30 (d, J=7.2 Hz, 1H), 7.26 (s, 1H), 5.78 (br s, 2H).MS: m/z 311.0 (M+H⁺).

Example 557: Synthesis of1-(4-(Benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea

Step 1: To a solution of benzo[d]thiazol-2-amine (2.0 g, 13.3 mmol) and1-bromo-4-nitrobenzene (4.03 g, 20.0 mmol) in DMSO (20 mL) was addedt-BuOK (2.24 g, 20.0 mmol). The resulting mixture was stirred at 80° C.overnight. Then to the reaction mixture was added H₂O (40 mL) andextracted with EA (40 mL×2). The combined organic layer was washed withbrine (40 mL×2) and concentrated in vacuum. The residue was purified bysilica gel column (PE/EA=100/1 to 30/1) to affordN-(4-nitrophenyl)benzo[d]thiazol-2-amine (1.96 g, yield 54%) as a yellowsolid.

Step 2: To a solution of N-(4-nitrophenyl)benzo[d]thiazol-2-amine (1.96g, 7.20 mmol) in MeOH (40 mL) was added Pd/C (392 mg, 20% wt). Theresulting mixture was stirred at room temperature under H₂ atmosphereovernight. Then Pd/C was filtered and the filtrate was concentrated invacuum. The residue was purified by silica gel column (DCM/MeOH=200/1 to40/1) to afford N¹-(benzo[d]thiazol-2-yl)benzene-1,4-diamine (976 mg,yield 56%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ=7.42 (d,J=7.8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.02-6.92 (m, 3H), 6.70 (d, J=8.4Hz, 2H), 6.38 (dt, J=7.8 Hz, 1H), 5.41 (br s, 2H).

Step 3: To a solution of N¹-(benzo[d]thiazol-2-yl)benzene-1,4-diamine(100 mg, 0.42 mmol) in dry DCM (20 mL) was added phenylcarbonochloridate (78 mg, 0.50 mmol) and followed by TEA (126 mg, 1.24mmol). The resulting mixture was stirred at room temperature for 1 hour.The reaction was monitored by TLC. Then the mixture was concentrated invacuum. The residue was purified by silica gel column (PE/EA=200/1 to30/1) to afford phenyl (4-(benzo[d]thiazol-2-ylamino)phenyl)carbamate(126 mg, yield 84%) as a white solid.

Step 4: To a solution of phenyl(4-(benzo[d]thiazol-2-ylamino)phenyl)carbamate (126 mg, 0.35 mmol) inACN (20 mL) was added oxazol-5-ylmethanamine (56.3 mg, 0.42 mmol, HClsalt) and followed by TEA (106 mg, 1.05 mmol). The resulting mixture wasstirred at 80° C. for 3 hours. The reaction was monitored by LC-MS. Thenthe mixture was concentrated in vacuum. The residue was purified byprep-HPLC with NH₄OH as additive to afford1-(4-(benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea (61.0mg, yield 48%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.99 (brs, 1H), 8.30 (br s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.45 (d, J=7.6 Hz, 1H),7.25 (d, J=8.4 Hz, 2H), 7.09 (t, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.99 (t,J=7.6 Hz, 1H), 6.81 (t, J=5.6 Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 4.40 (d,J=5.6 Hz, 2H). MS: m/z 366.0 (M+H⁺).

Example 558: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-ylamino)phenyl)urea

The title compound was prepared as described in example1-(4-(benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.62 (br s, 1H), 8.82 (br s, 1H), 8.16 (br s,1H), 7.59 (d, J=8.8 Hz, 2H), 7.57-7.50 (m, 2H), 7.47 (d, J=7.6 Hz, 1H),7.25 (d, J=8.8 Hz, 2H), 7.11 (t, J=8.0 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H),6.50 (t, J=5.2 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.18 (d, J=5.6 Hz, 2H).MS: m/z 365.1 (M+H⁺).

Example 559: Synthesis of 1-(4-(Benzo[d]thiazol-2-ylamino)phenyl)urea

The title compound was prepared as described in example1-(4-(benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=8.87 (br s, 1H), 8.18 (br s, 1H), 7.59 (d,J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.11 (t,J=8.4 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H), 6.43 (d, J=8.4 Hz, 1H), 5.97(brs, 2H). MS: m/z 285.0 (M+H⁺).

Example 560: Synthesis of1-(4-((5-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1 to 2: To a solution of 2-phenylacetaldehyde (120 mg, 1.0 mmol) indioxane (10 mL) was added Br₂ (176 mg, 1.1 mmol) at 0° C. The resultingmixture was stirred at 0° C. for 10 min and then at room temperature foranother 10 min. Then the mixture was concentrated in vacuum. The residuewas dissolved in EtOH (20 mL) and 1-phenylthiourea (197 mg, 1.0 mmol)was added. The resulting mixture was stirred at 80° C. overnight. Thereaction was monitored by TLC and LC-MS. The mixture was concentrated invacuum. The residue was purified by silica gel column (PE/EA=100/1 to30/1) to afford N-(4-nitrophenyl)-5-phenylthiazol-2-amine (126 mg, yield42%) as a yellow solid.

Step 3: To a solution of N-(4-nitrophenyl)-5-phenylthiazol-2-amine (126mg, 0.42 mmol) in MeOH (20 mL) was added Pd/C (25 mg, 20% wt). Theresulting mixture was stirred at room temperature under H₂ atmosphereovernight. The reaction was monitored by LC-MS. Then Pd/C was filteredand the filtrate was concentrated in vacuum to affordN¹-(5-phenylthiazol-2-yl)benzene-1,4-diamine (92 mg, yield 81%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.74 (br s, 1H), 7.58 (br s,1H), 7.46 (d, J=7.2 Hz, 2H), 7.35 (t, J=8.0 Hz, 2H), 7.28-7.14 (m, 3H),6.56 (d, J=8.8 Hz, 2H), 4.94 (br s, 2H).

Step 4: To a solution of N¹-(5-phenylthiazol-2-yl)benzene-1,4-diamine(300 mg, 1.12 mmol) in dry DCM (20 mL) was added phenylcarbonochloridate (351 mg, 2.24 mmol) and followed by TEA (341 mg, 3.36mmol). The resulting mixture was stirred at room temperature for 1 hour.The reaction was monitored by TLC. Then the mixture was concentrated invacuum. The residue was purified by silica gel column (DCM/MeOH=50/1) toafford phenyl (4-((5-phenylthiazol-2-yl)amino)phenyl)carbamate (342 mg,yield 79%) as a white solid.

Step 5: To a solution of phenyl(4-((5-phenylthiazol-2-yl)amino)phenyl)carbamate (100 mg, 0.26 mmol) inACN (20 mL) was added pyridin-4-ylmethanamine (56 mg, 0.52 mmol) and TEA(78 mg, 0.77 mmol). The resulting mixture was stirred at 80° C. for 3hrs. The reaction was monitored by LC-MS. Then the mixture wasconcentrated in vacuum. The residue was purified by prep-HPLC withNH₄HCO₃ as additive to afford1-(4-((5-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea(42.9 mg, yield 41%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=10.12 (br s, 1H), 8.59 (br s, 1H), 8.51 (d, J=6.0 Hz, 2H), 7.64 (s,1H), 7.56-7.46 (m, 4H), 7.43-7.33 (m, 4H), 7.29 (d, J=6.0 Hz, 2H), 7.23(t, J=7.6 Hz, 1H), 6.66 (t, J=6.0 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H). MS:m/z 402.1 (M+H⁺).

Example 561: Synthesis of1-(Oxazol-5-ylmethyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea

The title compound was prepared as described in example1-(4-((5-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=10.12 (br s, 1H), 8.46 (br s, 1H), 8.28 (s,1H), 7.64 (s, 1H), 7.55-7.46 (m, 4H), 7.42-7.30 (m, 4H), 7.24 (d, J=7.6Hz, 1H), 7.00 (s, 1H), 6.54 (t, J=5.6 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H).MS: m/z 392.1 (M+H⁺).

Example 562: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea

The title compound was prepared as described in example1-(4-((5-phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.61 (br s, 1H), 10.11 (br s, 1H), 8.31 (s,1H), 7.64 (s, 1H), 7.60-7.43 (m, 6H), 7.42-7.28 (m, 4H), 7.23 (d, J=7.2Hz, 1H), 6.24 (t, J=5.6 Hz, 1H), 4.14 (d, J=4.8 Hz, 2H). MS: m/z 391.0(M+H⁺).

Example 563: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea

Step 1: To a solution of 4-o-tolyl-thiazol-2-ylamine (460 mg, 2.42 mmol)in DMF (5 mL) was added 1-Fluoro-4-nitro-benzene (375.5 mg, 2.66 mmol)and CsCO₃ (2.36 g, 7.26 mmol). The reaction mixture was stirred at 120°C. under N₂ for 2 hrs. The reaction was quenched with water (40 mL) andextracted with EA (40 mL×3). The combined organic layer wasconcentrated. The residue was purified by flash column (PE/EA=4/1) togive (4-nitro-phenyl)-(4-o-tolyl-thiazol-2-yl)-amine (477 mg, yield 63%)as a yellow solid. MS: m/z 312.3 (M+H⁺)

Step 2: To a solution of (4-nitro-phenyl)-(4-o-tolyl-thiazol-2-yl)-amine(300 mg, 0.96 mmol) in EtOH (20 mL) and H₂O (5 mL) was added Fe (269 mg,4.82 mmol) and NH₄Cl (258 mg, 4.82 mmol). The reaction mixture wasstirred at 80° C. under N₂ for 1 hr. The reaction was completed detectedby LC-MS. The reaction was filtered. The filterate was concentrated andpurified by flash column to given-(4-o-tolyl-thiazol-2-yl)-benzene-1,4-diamine (0.172 g, yield 63%) as agray solid. MS: m/z 282.5 (M+H⁺)

Step3: To a solution of n-(4-o-tolyl-thiazol-2-yl)-benzene-1,4-diamine(98 mg, 0.348 mmol) in DCM (5 mL) was added pyridine (82.6 mg, 1.046mmol) and phenyl chloroformate (48.2 mg, 0.348 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 30 min. The reaction wascompleted detected by LC-MS. The reaction was concentrated to give thecrude [4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-carbamic acid phenylester. MS: m/z 402.4 (M+H⁺).

Step 4: To a solution of[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-carbamic acid phenyl ester (140mg, 0.348 mmol) in ACN (5 mL) was added TEA (105.5 mg, 1.044 mmol) andc-(1 h-pyrazol-4-yl)-methylamine (40 mg, 0.418 mmol). The reactionmixture was stirred at 80° C. under N₂ for 1.5 hrs. The reaction wascompleted detected by LC-MS. The reaction was concentrated and purifiedby prep-HPLC (NH₃.H₂O system) to afford 1-(1h-pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea(24.2 mg, yield 17%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=12.59 (s, 1H), 10.01 (s, 1H), 8.26 (s, 1H), 7.62-7.50 (m, 5H),7.33-7.23 (m, 5H), 6.88 (s, 1H), 6.23 (t, J=5.6 Hz, 1H), 4.13 (d, J=5.2Hz, 2H), 2.46 (s, 3H). MS: m/z 405.1 (M+H⁺).

Example 564: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-m-tolyl-thiazol-2-ylamino)-phenyl]-urea

The title compound was prepared using general procedure of1-(h-pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 10.04 (s, 1H), 8.29 (s, 1H),7.70 (d, J=8.4 Hz, 2H), 7.56-7.30 (m, 7H), 7.22 (s, 1H), 7.12 (d, J=7.2Hz, 1H), 6.26 (s, 1H), 4.14 (d, J=5.2 Hz, 2H), 2.37 (s, 3H). MS: m/z405.1 (M+H⁺)

Example 565: Synthesis of1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-p-tolyl-thiazol-2-ylamino)-phenyl]-urea

The title compound was prepared using general procedure of1-(h-pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 10.02 (s, 1H), 8.28 (s, 1H),7.79 (d, J=8 Hz, 2H), 7.60-7.46 (m, 4H), 7.35 (d, J=8.4 Hz, 2H), 7.22(d, J=7.6 Hz, 2H), 7.18 (s, 1H), 6.25 (t, J=5.2 Hz, 1H), 4.14 (d, J=5.2Hz, 2H), 2.33 (s, 3H). MS: m/z 405.1 (M+H⁺).

Example 566: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

The title compound was prepared using general procedure of1-(h-pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea.¹H NMR (400 MHz, DMSO-d₆): δ=9.99 (s, 1H), 8.29 (s, 1H), 8.14 (d, J=8.0Hz, 1H), 7.56-7.53 (m, 4H), 7.36-7.29 (m, 4H), 7.12-7.05 (m, 2H), 6.28(brs, 1H), 4.14 (s, 2H), 3.91 (s, 3H). MS: m/z 421.1 (M+H⁺).

Example 567: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(3-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=10.05 (s, 1H), 8.29 (s, 1H), 7.55-7.44 (m,6H), 7.36-7.28 (m, 4H), 6.90-6.86 (m, 1H), 6.35-6.25 (m, 1H), 4.14 (s,2H), 3.81 (s, 3H). MS: m/z 421.1 (M+H⁺).

Example 568: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(4-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea

The title compound was prepared using general procedure of1-((1H-pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=10.05 (s, 1H), 8.29 (s, 1H), 7.55-7.53 (m,4H), 7.50-7.48 (m, 1H), 7.45-7.43 (m, 1H), 7.36-7.33 (m, 3H), 7.31-7.28(m, 1H), 6.90-6.88 (m, 1H), 6.30-6.20 (m, 1H), 4.14 (s, 2H), 3.81 (s,3H), m/z 421.1 (M+H⁺).

Example 569: Synthesis of1-[4-(Benzothiazol-2-ylamino)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of benzothiazol-2-ylamine (901 mg, 6.0 mmol) inDMSO (30 mL) was added 1-bromo-4-nitro-benzene (1.3 g, 6.6 mmol) andt-BuOK (740.5 mg, 6.6 mmol). The mixture was stirred at 80° C.overnight. The reaction was monitored by LCMS. After cooling andaddition of water (30 mL), a suspension was generated which wasextracted with EA (100 mL). The combined organic layer was dried oversodium sulfate anhydrous, filtered and concentrated in vacuum. Theresidue was purified by flash column to affordbenzothiazol-2-yl-(4-nitro-phenyl)-amine (804 mg, yield 49%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.65 (s, 1H), 8.41 (d, J=8.8 Hz,2H), 7.79 (d, J=8.8 Hz, 2H), 7.51 (d, J=6.8 Hz, 1H), 7.12 (t, J=7.6 Hz,1H), 7.08 (t, J=7.2 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H).

Step 2: To a solution of benzothiazol-2-yl-(4-nitro-phenyl)-amine (404mg, 1.48 mmol) in EtOH (25 mL) and H₂O (5 mL) was added NH₄Cl (395.83mg, 7.4 mmol) and iron powder (13.29 mg, 7.4 mmol). The reaction mixturewas stirred at 80° C. overnight. Iron powder was filtered off and thefiltrate was concentrated in vacuum. The residue was purified by flashto give n-benzothiazol-2-yl-benzene-1,4-diamine (134 mg, yield 39%) as ayellow solid.

Step 3: To a solution of n-benzothiazol-2-yl-benzene-1,4-diamine (134mg, 0.55 mmol) in DCM (30 mL) was added phenyl chloroformate (87.05 mg,0.55 mmol) and TEA (111.31 mg, 1.1 mmol). The mixture was stirred at 0°C. for 1 hr. The reaction was monitored by TLC. After completion, themixture was concentrated in vacuum. The residue was purified by a silicagel column (PE/EA=3/1) to afford[4-(benzothiazol-2-ylamino)-phenyl]-carbamic acid phenyl ester (80.3 mg,yield 41%) as a yellow solid.

Step 4: To a solution of [4-(benzothiazol-2-ylamino)-phenyl]-carbamicacid phenyl ester (80 mg, 0.22 mmol) in ACN (20 mL) was addedc-pyridin-4-yl-methylamine (30.27 mg, 0.28 mmol) and TEA (44.53 mg, 0.44mmol). The mixture was stirred at 80° C. for 3 hrs. The reaction wasmonitored by LCMS. After completion, the mixture was concentrated invacuum. The residue was purified by prep-HPLC to give 1-[4-(1h-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea (6.7 mg, yield 3%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.62 (s, 1H), 8.51 (d, J=5.2Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.32 (d, J=5.6Hz, 3H), 7.24 (d, J=8.8 Hz, 3H), 7.10 (t, J=7.6 Hz, 1H), 6.99 (t, J=6.4Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H). MS: m/z 376.0(M+H⁺).

Example 570: Synthesis of1-{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

Step 1: To a solution of 2-bromo-1-(4-fluoro-phenyl)-ethanone (1.5 g,6.9 mmol) and thiourea (524 mg, 6.9 mmol) in EtOH (10 mL) was stirred at82° C. under N₂ for 3 hrs. The reaction was concentrated in vacuum. Theresidue was purified by slurry in EA to give4-(4-fluoro-phenyl)-thiazol-2-ylamine (1 g, crude, yield: quantitative)as a white solid. MS: m/z 195.3 (M+H⁺).

Step 2: To a solution of 4-(4-fluoro-phenyl)-thiazol-2-ylamine (1.0 g,5.2 mmol) in DMF (10 mL) was added 1-fluoro-4-nitro-benzene (806.5 mg,5.7 mmol) and CsCO₃ (5.07 g, 15.6 mmol). The reaction was stirred at 80°C. under N₂ for 2 hrs. The reaction was quenched with water (40 mL) andextracted with EA (40 mL×3). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel column (PE/EA=10/1) to give[4-(4-fluoro-phenyl)-thiazol-2-yl]-(4-nitro-phenyl)-amine (990 mg, yield60%) as a yellow solid. MS: m/z 316.4 (M+H⁺).

Step 3: To a solution of[4-(4-fluoro-phenyl)-thiazol-2-yl]-(4-nitro-phenyl)-amine (990 mg, 3.14mmol) in EtOH (30 mL) and water (6 mL) was added iron powder (880 mg,15.7 mmol) and NH₄Cl (840 mg, 15.7 mmol). The reaction mixture wasstirred at 80° C. under nitrogen for 1 hr. The iron powder was filtered.The organic layer was concentrated in vacuum. The mixture was extractedwith ethyl acetate (50 mL×2). The combined organic layer was washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by silica gel column (PE/EA=10/1) to giveN-[4-(4-fluoro-phenyl)-thiazol-2-yl]-benzene-1, 4-diamine (550 mg, yield62%) as a brown solid. MS: m/z 286.4 (M+H⁺).

Step 4: To a solution of N-[4-(4-fluoro-phenyl)-thiazol-2-yl]-benzene-1,4-diamine (200 mg, 0.7 mmol) in DCM (7 mL) was added pyridine (165.9 mg,2.1 mmol). The mixture was cooled to 0° C. and added phenylchloroformate (120.6 mg, 0.77 mmol) dropwise. The reaction was stirredat room temperature for 0.5 hr. The mixture was washed with water (50mL×2). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gel column(PE/EA=10/1) to give{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-carbamic acid phenylester (94 mg, yield 33%) as a brown solid. MS: m/z 406.4 (M+H⁺).

Step 5: To a solution of{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-carbamic acid phenylester (94 mg, 0.23 mmol) and C-(1H-Pyrazol-4-yl)-methylamine (26.8 mg,0.276 mmol) in acetonitrile (5 mL) was added TEA (69.7 mg, 0.69 mmol).The reaction was stirred at 80° C. for 1.5 hrs. The acetonitrile wasremoved in vacuum. The mixture was washed with DCM (2 mL) and filtered.The solid was purified by prep-HPLC to give1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea(19.2 mg, yield 21%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ=12.57 (s, 1H), 10.07 (s, 1H), 8.29 (s, 1H), 7.95 (dd, J=8.8, 5.6 Hz,2H), 7.57-7.52 (m, 4H), 7.35 (d, J=8.8 Hz, 2H), 7.27-7.23 (m, 3H), 6.26(t, J=5.2 Hz, 1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 409.1 (M+H⁺).

Example 571: Synthesis of1-{4-[4-(2-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (s, 1H), 10.10 (s, 1H), 8.30 (s, 1H),8.13-8.10 (m, 1H), 7.57-7.29 (m, 9H), 7.19 (d, J=2.4 Hz, 1H), 6.27-6.24(m, 1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 409.1 (M+H⁺).

Example 572: Synthesis of1-{4-[4-(3-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆) δ=12.56 (s, 1H), 10.09 (s, 1H), 8.29 (s, 1H),7.76 (d, J=8.0 Hz, 1H), 7.71-7.68 (m, 1H), 7.56-7.45 (m, 5H), 7.40-7.35(m, 3H), 7.13 (d, J=2.0 Hz, 1H), 6.26 (s, 1H), 4.14 (d, J=5.6 Hz, 2H).MS: m/z 409.0 (M+H⁺).

Example 573: Synthesis of1-{4-[4-(2-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.60 (s, 1H), 10.11 (s, 1H), 8.50 (s, 1H),7.93 (dd, J=7.6, 2.0 Hz, 1H), 7.54-7.44 (m, 6H), 7.37-7.33 (m, 3H), 7.28(s, 1H), 6.39 (s, 1H), 4.14 (d, J=5.2 Hz, 2H). MS: m/z 425.0 (M+H⁺).

Example 574: Synthesis of1-{4-[4-(3-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=10.10 (s, 1H), 8.31 (s, 1H), 7.93 (d, J=1.6Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.56-7.53 (m, 4H), 7.48-7.43 (m, 2H),7.38-7.35 (m, 3H), 6.28 (s, 1H), 4.15 (s, 2H). MS: m/z 425.0 (M+H⁺).

Example 575: Synthesis of1-{4-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-{4-[4-(4-fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea.¹H NMR (400 MHz, DMSO-d₆): δ=10.08 (s, 1H), 8.30 (s, 1H), 7.93 (d, J=8.4Hz, 2H), 7.56-7.54 (m, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.37-7.33 (m, 3H),6.27 (s, 1H), 4.15 (s, 2H). MS: m/z 425.0 (M+H⁺).

Example 576: Synthesis ofN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p-tolyl-methanesulfonamide

Step 1: To a solution of 4-nitro-phenylamine (10 g, 72.4 mmol) andpyridine (15.4 g, 195.5 mmol) in DCM (400 mL) was added phenylchloroformate (15.8 g, 101.36 mmol) slowly under 0° C. The reactionmixture was stirred at room temperature for 2 hrs. The reaction mixturewas filtered. The filtrate was concentrated and purified by flash column(PE/EA=10/1) to give (4-nitro-phenyl)-carbamic acid phenyl ester (16.06g, yield 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.19 (d,J=9.2 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.47 (s, 1H), 7.43-7.39 (m, 2H),7.29-7.25 (m, 1H), 7.19 (d, J=7.6 Hz, 2H).

Step 2: A mixture of (4-Nitro-phenyl)-carbamic acid phenyl ester (10.0g, 38.75 mmol), C-Pyridin-4-yl-methylamine (4.188 g, 38.75 mmol) and TEA(7.82 g, 77.5 mmol) in ACN (100 mL) was stirred at 80° C. under N₂overnight. The reaction solution was filtered. The filter cake waswashed with ACN (50 mL) to give1-(4-nitro-phenyl)-3-pyridin-4-ylmethyl-urea (10.22 g, yield 95%) as awhite solid. MS: m/z 273.1 (M+H⁺).

Step 3: To a solution of 1-(4-nitro-phenyl)-3-pyridin-4-ylmethyl-urea(5.0 g, 18.4 mmol) in MeOH (50 mL) was added Pd/C (10% wet, 1 g). Thereaction mixture was stirred at room temperature under H₂ (3 atm)overnight. The reaction solution was filtered. The filtrate wasconcentrated to give the crude1-(4-amino-phenyl)-3-pyridin-4-ylmethyl-urea (4.42 g, yield 99.5%) as ayellow solid. MS: m/z 243.0 (M+H⁺)

Step 4: A solution of 1-(4-Amino-phenyl)-3-pyridin-4-ylmethyl-urea (80mg, 0.33 mmol) in DMF (3 mL) was added p-Tolyl-methanesulfonyl chloride(94.7 mg, 0.46 mmol) and TEA (168.4 mg, 1.65 mmol). The reaction mixturewas stirred at room temperature overnight. The mixture was washed H₂O(10 mL) and extracted with EA (50 mL). The combined organic phase wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby prep-HPLC (5-95; NH₄HCO₃) to given-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-c-p-tolyl-methanesulfonamide(35 mg, yield 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.49(s, 1H), 8.68 (s, 1H), 8.51-8.49 (m, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.28(d, J=5.6 Hz, 2H), 7.18-7.13 (m, 4H), 7.08 (d, J=8.8 Hz, 2H), 6.71 (t,J=5.6 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 4.29 (s, 2H), 2.29 (s, 3H). MS:m/z 410.9 (M+H⁺).

Example 577: Synthesis ofN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-m-tolyl-methanesulfonamide

The title compound was prepared using general procedure ofN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p-tolyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.52 (s, 1H), 8.69 (s, 1H), 8.50 (d, J=6.0Hz, 2H), 7.41-7.33 (m, 2H), 7.31-7.26 (m, 2H), 7.25-7.21 (m, 1H), 7.15(d, J=8.0 Hz, 1H), 7.10-7.03 (m, 4H), 6.72 (t, J=5.6 Hz, 1H), 4.32 (d,J=6.0 Hz, 2H), 4.30 (s, 2 H), 2.28 (s, 3H). MS: m/z 411.0 (M+H⁺).

Example 578: Synthesis of1-[4-(2-Methyl-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure ofN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p-tolyl-methanesulfonamide.¹H NMR (400 MHz, CD₃OD): δ=8.48-8.46 (m, 2H), 7.40 (d, J=6.4 Hz, 2H),7.35 (d, J=6.8 Hz, 2H), 7.21-7.12 (m, 6H), 4.45 (s, 2H), 4.39 (s, 2H),2.33 (s, 3H). MS: m/z 410.8 (M+H⁺).

Example 579: Synthesis ofC-(4-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

Step 1: A mixture of 1-bromo-4-bromomethyl-benzene (2.0 g, 8.0 mmol) andthioacetic acid S-(4-bromo-benzyl) ester (1.37 g, 12 mmol) in acetone(50 mL) was heated to reflux for 16 hrs. The mixture was cooled andfiltered. The filtrate was concentrated and the residue was purified bysilica gel column chromatography (PE/EA=10/1) to give(4-bromo-phenyl)-methanesulfonyl chloride (1.7 g, yield 87%) as brownoil. ¹H NMR (400 MHz, CDCl₃): δ=7.41 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 4.05 (s, 2H), 2.35 (s, 3H).

Step 2: To a solution of HCl (2M, 1.547 mL) in MeCN (30 mL) was addedNCS (3.3 g, 24.6 mmol) at 0° C. in portions. The resulting mixture wasstirred for 5 min at 0° C. Then to this mixture was added a solution of(4-bromo-phenyl)-methanesulfonyl chloride (1.5 g, 6.15 mmol) in MeCN (3mL) dropwise at 0° C. during 1 min. The reaction mixture was stirred for10 min. Na₂SO₄ (about 5 g) was added and the mixture was filtered. Thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (PE/EA=10/1) to give (4-bromo-phenyl)-methanesulfonylchloride (1.2 g, yield 73%) as a white solid. ¹H NMR (300 MHz, CDCl₃):δ=7.62 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.83 (s, 2H).

Step 3: A mixture of (4-bromo-phenyl)-methanesulfonyl chloride (470 mg,1.73 mmol), 1-(4-amino-phenyl)-3-pyridin-4-ylmethyl-urea (300 mg, 1.24mmol) and TEA (0.9 mL, 6.2 mmol) in DMF (10 mL) was stirred at 80° C.for 14 hrs. The mixture was diluted with water (30 mL) and extractedwith EA (30 mL×3). The combined organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography (DCM/MeOH=30/1 to 15/1) to giveC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(270 mg, yield 46%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47(d, J=6.1 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.40 (d, J=5.9 Hz, 2H),7.37-7.30 (m, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.15-7.08 (m, 2H), 4.45 (s,2H), 4.32 (s, 2H). MS: m/z 475.1 (M+H⁺).

Example 580: Synthesis ofC-(4-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

A mixture ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(24 mg, 0.05 mmol), Pd₂dba₃ (8 mg, 0.008 mmol), ^(t)BuXPhos (8 mg, 0.019mmol) and ^(t)BuONa (24 mg, 0.25 mmol) in dioxane (1.5 mL) and dry MeOH(0.5 mL) was heated at 95° C. for 16 hrs under Ar. The reaction mixturewas concentrated. The residue was purified by prep-TLC (DCM/MeOH=10/1)to giveC-(4-methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(10 mg, yield 9%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (d,J=5.6 Hz, 2H), 7.40 (d, J=5.3 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.19 (d,J=8.5 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.45 (s,2H), 4.27 (s, 2H), 3.77 (s, 3H). MS: m/z 427.1 (M+H⁺).

Example 581: Synthesis ofC-(4-Cyclopropyl-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

A mixture ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(47 mg, 0.1 mmol), cyclopropylboronic acid (26 mg, 0.3 mmol),Pd(dppf)Cl₂ (8 mg, 0.01 mmol), K₂CO₃ (42 mg, 0.3 mmol) and KF.2H₂O (28mg, 0.3 mmol) in dioxane (3 mL) and water (0.5 mL) was heated to 110° C.for 16 hrs under N₂. The resulting mixture was concentrated. The residuewas purified by prep-TLC (DCM/MeOH=10/1) to giveC-(4-cyclopropyl-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(5.5 mg, yield 13%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47(d, J=6.2 Hz, 2H), 7.40 (d, J=6.1 Hz, 2H), 7.33 (d, J=8.9 Hz, 2H), 7.15(d, J=8.1 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 4.45(s, 2H), 4.28 (s, 2H), 1.95-1.83 (m, 1H), 0.99-0.92 (m, 2H), 0.68-0.62(m, 2H). MS: m/z 437.2 (M+H⁺).

Example 582: Synthesis ofC-Biphenyl-4-yl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

To a solution ofC-(4-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(50 mg, 0.105 mmol) in dioxane (4 mL) and H₂O (0.7 mL) was addedphenylboronic acid (25 mg, 0.21 mmol), K₂CO₃ (72 mg, 0.525 mmol) and Pd(dppf) Cl₂ (7.6 mg, 0.0105 mmol). The mixture was stirred at 110° C.overnight. The reaction was concentrated and the residue was purified byTLC (DCM/MEOH=10/1) to giveC-Biphenyl-4-yl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(52 mg, yield 81%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (d,J=4.4 Hz, 2H), 7.60-7.56 (m, 4H) 7.44-7.32 (m, 9H), 7.14 (t, J=6.8 Hz,2H), 4.45 (s, 2H), 4.39 (s, 2H). MS: m/z 472.8 (M+H⁺).

Example 583: Synthesis ofC-(4-Cyano-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

A mixture ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(60 mg, 0.126 mmol), Zn(CN)₂ (74 mg, 0.63 mmol) and Pd(PPh₃)₄ (15 mg,0.013 mmol) in DMF (2 mL) was stirred at 150° C. for 1.5 hrs in a sealedmicrowave under N₂. The mixture was diluted with water (20 mL) andextracted with EA (15 mL×3). The combined organic layer wasconcentrated. The residue was purified by prep-TLC (DCM/MeOH=10/1) togiveC-(4-cyano-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(15 mg, yield 28%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.47 (d,J=6.1 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.40 (d,J=6.0 Hz, 2H), 7.34 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 4.50-4.40(m, 4H). MS: m/z 421.9 (M+H⁺).

Example 584: Synthesis of1-[4-(3-Bromo-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=6.4 Hz, 2H), 7.49 (m, 2H), 7.40(d, J=5.6 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.27-7.22 (m, 2H), 7.12 (d,J=8.8 Hz, 2H), 4.45 (s, 2H), 4.34 (s, 2H). MS: m/z 474.7 (M+H⁺).

Example 585: Synthesis ofC-(3-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

A mixture ofC-(3-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(50 mg, 0.105 mmol), Pd₂(dba)₃ (19 mg 0.021 mmol), t-Buxphos (18 mg0.042 mmol) and t-BuONa (50 mg 0.525 mmol) in dioxane (1.5 mL) and MeOH(0.5 mL) was stirred at 95° C. in microwave tube overnight. The reactionmixture was cooled to r.t and concentrated. The residue was purified byprep-HPLC to getC-(3-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(14 mg, yield 31%) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ=8.45 (d,J=4.4 Hz, 2H), 7.40 (d, J=6.0 Hz, 2H), 7.34 (d, J=6.8 Hz, 2H), 7.25-7.21(m, 1H), 7.12 (d, J=6.8 Hz, 2H), 6.89-6.83 (m, 3H), 4.45 (s, 2H) 4.31(s, 2H), 3.74 (s, 3H). MS: m/z 426.9 (M+H⁺).

Example 586: Synthesis ofC-(2-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

The title compound was prepared using general procedure ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ=9.76 (s, 1H), 8.68 (s, 1H), 8.50 (d, J=5.2Hz, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.41 (d, J=4 Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.31-7.27 (m, 3H), 7.11 (d, J=9.2 Hz, 2H), 6.71 (t, J=5.6 Hz,1H), 4.54 (s, 2H), 4.32 (d, J=5.6 Hz, 2H). MS: m/z 475.0 (M+H⁺).

Example 587: Synthesis ofC-(2-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

A mixture ofC-(2-bromo-phenyl)-n-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(24 mg, 0.05 mmol), Pd₂dba₃ (8 mg, 0.008 mmol), tBuxphos (8 mg, 0.019mmol) and tBuONa (24 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) and MeOH(0.5 mL) was stirred at 95° C. under Ar overnight. The reaction wasrepeated five times. All of the solution was concentrated and purifiedby prep-TLC (DCM/MeOH=10/1) and prep-HPLC (5-95; NH₄HCO₃) to affordC-(2-methoxy-phenyl)-n-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide(1.3 mg, yield 1%) as a yellow solid. ¹H NMR (800 MHz, CD₃OD): 8.38 (d,J=6.0 Hz, 2H), 7.31 (d, J=6.0 Hz, 2H), 7.22-7.18 (m, 4H), 7.00-6.97 (m,2H), 6.82-6.80 (m, 2H), 4.35 (s, 4H), 3.55 (s, 3H). MS: m/z 427.0(M+H⁺).

Example 588: Synthesis of1-[4-(4-Fluoro-phenylmethanesulfonyl)-phenyl]-3-(1H-pyrazol-4-yl)-urea

The title compound was prepared using general procedure ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ=9.56 (s, 1H), 8.72 (s, 1H), 8.51 (d, J=5.6Hz, 2H), 7.38-7.27 (m, 6H), 7.22-7.18 (m, 2H), 7.08-7.06 (m, 2H),6.74-6.71 (m, 1H), 4.38 (s, 2H), 4.32 (d, J=6.0 Hz, 2H). MS: m/z 414.9(M+H⁺).

Example 589: Synthesis ofC-(3-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

The title compound was prepared using general procedure ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ=9.60 (s, 1H), 8.69 (s, 1H), 8.51-8.49 (m,2H), 7.43-7.35 (m, 3H), 7.29-7.28 (m, 2H), 7.22-7.17 (m, 1H), 7.11-7.07(m, 4H), 6.71-6.69 (m, 1H), 4.42 (s, 2H), 4.32 (d, J=6.0 Hz, 2H). MS:m/z 415.1 (M+H⁺).

Example 590: Synthesis ofC-(2-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide

The title compound was prepared using general procedure ofC-(4-bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide.¹H NMR (400 MHz, CD₃OD): δ=8.47 (d, J=6.2 Hz, 2H), 7.45-7.27 (m, 6H),7.18-7.05 (m, 4H), 4.48-4.38 (m, 4H). MS: m/z 414.9 (M+H⁺).

Example 591: Synthesis of1-(3-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

Step 1: A solution of phenyl (4-nitrophenyl)carbamate (500 mg, 1.94mmoL), oxazol-5-ylmethanamine hydrochloride (261 mg, 1.94 mmoL) and Et₃N(1 mL, 6.93 mmoL) in MeCN (16 mL) was refluxed for 1 hr. The reactionmixture was concentrated to dryness in vacuum and the residue waspurified by silica gel column (DCM/MeOH=40/1) to give1-(4-nitro-phenyl)-3-oxazol-5-ylmethyl-urea (480 mg, yield: 94%) as awhite solid.

Step 2: A suspension of 1-(4-nitro-phenyl)-3-oxazol-5-ylmethyl-urea (900mg, 3.44 mmoL) and 10% Pd/C (190 mg) in MeOH (25 mL) was stirred for 19hrs at room temperature under H₂ atmosphere (balloon). The reactionmixture was filtered to remove catalyst and the filtrate wasconcentrated to dryness in vacuum to give1-(4-amino-phenyl)-3-oxazol-5-ylmethyl-urea (670 mg, yield 84%) as a redsolid. MS: m/z 233.0 (M+H⁺).

Step 3: To a solution of 1-(4-amino-phenyl)-3-oxazol-5-ylmethyl-urea(100 mg, 0.43 mmoL) and Et₃N (0.1 mL, 0.69 mmoL) in DMF (2.5 mL) wasadded (3-chloro-phenyl)-methanesulfonyl chloride (97 mg, 0.43 mmoL) at0° C. and the mixture was stirred for 19 hrs at room temperature. Thereaction mixture was poured into H₂O (18 mL) and extracted with EA (20mL×3).

The combined organic layer was washed with H₂O (50 mL) and brine (50mL), dried over Na₂SO₄, filtered and concentrated to dryness in vacuum.The residue was purified by silica flash column (4% MeOH in DCM) andtriturated with MeCN (2 mL) to give1-(3-chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide(71 mg, yield 39%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.62(s, 1H), 8.57 (s, 1H), 8.29 (s, 1H), 7.44-7.33 (m, 5H), 7.22 (d, J=7.2Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.59 (t, J=5.6 Hz, 1H),4.42 (s, 2H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 420.9 (M+H⁺).

Example 592: Synthesis of1-(4-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

The title compound was prepared using general procedure of1-(3-chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.56 (s, 1H), 8.57 (s, 1H), 8.29 (s, 1H),7.43 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H),7.07 (d, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.59 (t, J=6.0 Hz, 1H), 4.39-4.35(m, 4H). MS: m/z 420.9 (M+H⁺).

Example 593: Synthesis of1-(2-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

The title compound was prepared using general procedure of1-(3-chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.76 (s, 1H), 8.55 (s, 1H), 8.28 (s, 1H),7.49-7.47 (m, 1H), 7.42-7.32 (m, 5H), 7.10 (d, J=9.2 Hz, 2H), 7.00 (s,1H), 6.59 (t, J=6.0 Hz, 1H), 4.53 (s, 2H), 4.36 (d, J=5.6 Hz, 2H). MS:m/z 420.9 (M+H⁺).

Example 594: Synthesis of1-(3,4-Dichlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide

Step 1: A solution of 1, 2-dichloro-4-chloromethyl-benzene (1.0 g, 5.1mmoL) and potassium thioacetate (0.87 g, 7.6 mmol) in acetone (25 mL)was stirred at 65° C. for 19 hrs. The reaction mixture was filtered andthe filtrate was concentrated to dryness in vacuum. The residue waspurified by silica gel column (PE/EA=25/1) to give thioacetic acidS-(3,4-dichloro-benzyl) ester (1.25 g, crude) as brown oil. ¹H NMR (400MHz, CDCl₃): δ=7.38 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.12 (dd,J=8.0, 3.0 Hz, 1H), 4.04 (s, 2H), 2.36 (s, 3H).

Step 2: To a solution of concentrated HCl (0.5 mL) in MeCN (10 mL) wasadded NCS (1.14 g, 8.51 mmoL) at 0° C. The reaction mixture was stirredfor 15 min. Then a solution of thioacetic acid S-(3,4-dichloro-benzyl)ester (500 mg, 2.13 mmoL) in MeCN (1 mL) was added to the reactionmixture dropwise. Then the mixture was stirred at 0° C. for 30 min. Thereaction mixture was concentrated to dryness in vacuum and the residuewas purified by silica gel column (PE/EA=20/1) to give(3,4-dichloro-phenyl)-methanesulfonyl chloride (248 mg, yield 45%) as ayellow solid. ¹H NMR (300 MHz, CDCl₃): δ=7.60-7.55 (m, 2H), 7.35 (dd,J=8.1, 1.2 Hz, 1H), 4.82 (s, 2H).

Step 3: To a solution of 1-(4-amino-phenyl)-3-oxazol-5-ylmethyl-urea(100 mg, 0.43 mmoL) and Et₃N (0.1 mL, 0.69 mmoL) in DMF (3 mL) was added(3,4-dichloro-phenyl)-methanesulfonyl chloride (123 mg, 0.47 mmoL) at 0°C. The mixture was stirred at 35° C. for 7 hrs. The reaction mixture waspoured into H₂O (20 mL) and extracted with EA (20 mL×5). The combinedorganic layer was washed with H₂O (50 mL) and brine (60 mL×3), driedover Na₂SO₄, filtered and concentrated to dryness in vacuum. The residuewas purified by silica flash column (5% MeOH in DCM) and triturated withMeCN (2.5 mL) to giveC-(3,4-dichloro-phenyl)-N-[4-(3-oxazol-5-ylmethyl-ureido)-phenyl]-methanesulfonamide(41 mg, yield 21%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.62(s, 1H), 8.58 (s, 1H), 8.29 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.50 (d,J=2.0 Hz, 1H), 7.35 (dd, J=6.8, 1.6 Hz, 2H), 7.25 (dd, J=8.4, 2.0 Hz,1H), 7.06 (d, J=8.8 Hz, 2H), 7.00 (s, 1H), 6.59 (t, J=6.0 Hz, 1H), 4.45(s, 2H), 4.36 (d, J=5.6 Hz, 2H). MS: m/z 454.8 (M+H⁺).

Example 595: Synthesis ofC-(3-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

Step 1: A solution of 1H-pyrazole-4-carbaldehyde (2.05 g, 21.4 mmoL) andhydroxylamine hydrochloride (1.63 g, 23.5 mmol) in MeOH (50 mL) wasstirred at room temperature for 19 hrs. The reaction mixture wasconcentrated to give 1H-pyrazole-4-carbaldehyde oxime (3.3 g, crude) asa yellow solid.

Step 2: To a solution of 1H-pyrazole-4-carbaldehyde oxime (300 mg, 2.7mmol) in MeOH (25 mL) was added NH₃.H₂O (2 mL) and Raney-Ni (50 mg). Thesuspension was stirred at room temperature for 24 hrs under H₂atmosphere (balloon). The reaction mixture was filtered to remove mostof catalyst and the filtrate was concentrated to dryness in vacuum. Thenthe residue was diluted with MeOH (15 mL) and the mixture was filteredagain. The filtrate was concentrated to givec-(1H-pyrazol-4-yl)-methylamine (123 mg, yield 47%) as a green solid.

Step 3: To a solution of (4-amino-phenyl)-carbamic acid tert-butyl ester(150 mg, 0.72 mmol) and Et₃N (0.2 mL, 1.4 mmol) in DCM (5 mL) was added(3-chloro-phenyl)-methanesulfonyl chloride (178 mg, 0.79 mmoL) at 0° C.The reaction mixture was stirred at room temperature for 19 hrs. Thereaction mixture was concentrated to dryness in vacuum. Then the residuewas purified by silica gel column (PE/EA=5/1) to give[4-(3-chloro-phenylmethanesulfonylamino)-phenyl]-carbamic acidtert-butyl ester (128 mg, yield 45%) as a red solid.

Step 4: A solution of[4-(3-chloro-phenylmethanesulfonylamino)-phenyl]-carbamic acidtert-butyl ester (128 mg, 0.32 mmol) in HCl/MeOH (5 M, 5 mL, 25 mmol)was stirred at room temperature for 19 hrs. The reaction mixture wasconcentrated to dryness in vacuum and the residue was dissolved in EA(20 mL). The organic layer was washed with saturated aqueous NaHCO₃ (40mL), dried over Na₂SO₄, filtered and concentrated to giveN-(4-amino-phenyl)-C-(3-chloro-phenyl)-methanesulfonamide (95 mg, yield99%) as a white solid.

Step 5: To a solution ofN-(4-amino-phenyl)-C-(3-chloro-phenyl)-methanesulfonamide (95 mg, 0.32mmol) and pyridine (101 mg, 1.28 mmol) in DCM (5 mL) was added phenylchloroformate (65 mg, 0.42 mmol) at 0° C. The reaction mixture wasstirred for 30 min at 0° C. The reaction mixture was diluted with DCM(25 mL), washed with 1 M HCl (20 mL) and saturated aqueous NaHCO₃ (20mL), dried over Na₂SO₄, filtered and concentrated to dryness in vacuum.Then the residue was purified by silica flash column (19% EA in PE) togive [4-(3-chloro-phenylmethanesulfonylamino)-phenyl]-carbamic acidphenyl ester (98 mg, yield 74%) as a white solid.

Step 6: A solution of[4-(3-chloro-phenylmethanesulfonylamino)-phenyl]-carbamic acid phenylester (100 mg, 0.24 mmol), C-(1H-pyrazol-4-yl)-methylamine (103 mg, 1.06mmol) and Et₃N (0.5 mL, 3.5 mmol) in MeCN (10 mL) was stirred at 80° C.for 1 hr. The reaction mixture was concentrated to dryness in vacuum.The residue was dissolved in DMF (2 mL). H₂O (1 mL) was added into themixture and the resulting solid was collected by filtration. Then thepad was dissolved in DMF (1.5 mL) again and H₂O was added into themixture. The mixture was filtered and the pad was rinsed with H₂O togiveC-(3-chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide(19 mg, yield 19%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.60(s, 1H), 8.42 (s, 1H), 7.53 (s, 2H), 7.43-7.34 (m, 5H), 7.22 (d, J=7.2Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.30 (t, J=5.60 Hz, 1H), 4.42 (s, 2H),4.14 (d, J=5.2 Hz, 2H). MS: m/z 419.9 (M+H⁺).

Example 596: Synthesis ofC-(2-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

The title compound was prepared using general procedure ofC-(3-chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide.¹H NMR (400 MHz, CD₃OD): δ=7.60 (s, 2H), 7.45 (dd, J=7.2, 2.4 Hz, 1H),7.39 (dd, J=8.0, 2.4 Hz, 1H), 7.31-7.28 (m, 4H), 7.12 (dd, J=6.8, 2.0Hz, 2H), 4.57 (s, 2H), 4.28 (s, 2H). MS: m/z 419.9 (M+H⁺).

Example 597: Synthesis ofC-(4-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

The title compound was prepared using general procedure ofC-(3-chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.55 (s, 1H), 8.45 (s, 1H), 7.55 (s, 2H),7.43 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H),7.06 (d, J=9.2 Hz, 2H), 6.33 (s, 1H), 4.38 (s, 2H), 4.14 (d, J=2.4 Hz,2H). MS: m/z 419.9 (M+H⁺).

Example 598: Synthesis ofC-(3,4-Dichloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide

The title compound was prepared using general procedure ofC-(3-chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆): δ=9.60 (s, 1H), 8.45 (s, 1H), 7.65 (d, J=8.4Hz, 1H), 7.55-7.51 (m, 3H), 7.35 (d, J=8.8 Hz, 2H), 7.25 (dd, J=8.4, 2.0Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.45 (s, 2H), 4.14 (s,2H). MS: m/z 453.9 (M+H⁺).

Example 599: Synthesis ofN-(3-Fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

Step 1: To a solution of 3-fluoro-benzylamine (282.8 mg, 2.26 mmol) inDCM (20 mL) was added 4-nitro-benzenesulfonyl chloride (500.8 mg, 2.26mmol) and TEA (228.3 mg, 2.26 mmol). The mixture was stirred at roomtemperature for 1 hr. The mixture was concentrated in vacuum. Theresidue was purified by a silica gel column (DCM) to affordn-(3-fluoro-benzyl)-4-nitro-benzenesulfonamide (636.4 mg, yield 91%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.62 (t, J=6.0 Hz, 1H), 8.36(d, J=8.8 Hz, 2H), 8.00 (d, J=9.2 Hz, 2H), 7.33-7.27 (m, 1H), 7.07-7.00(m, 3H), 4.10 (d, J=6.4 Hz, 2H).

Step 2: To a solution of n-(3-fluoro-benzyl)-4-nitro-benzenesulfonamide(636.4 mg, 2.1 mmol) in MeOH (30 mL) was added Pd/C (10% wet, 93.3 mg).The reaction mixture was stirred at room temperature under H₂ (1 atm)for 3 hrs. Pd/C was filtered off and the filtrate was concentrated todryness in vacuum. The residue was purified by flash to give4-amino-n-(3-fluoro-benzyl)-benzenesulfonamide (474 mg, yield 81%) as awhite solid.

Step 3: To a solution of 4-amino-n-(3-fluoro-benzyl)-benzenesulfonamide(300 mg, 1.07 mmol) in DCM (30 mL) was added phenyl chloroformate(502.59 mg, 3.21 mmol) and TEA (324.85 mg, 3.21 mmol). The mixture wasstirred at 0° C. for 1 hr. The reaction mixture was concentrated invacuum. The residue was purified by a silica gel column (PE/EA=3/1) toafford [4-(3-fluoro-benzylsulfamoyl)-phenyl]-carbamic acid phenyl ester(256.7 mg, yield 60%) as a white solid.

Step 4: To a solution of [4-(3-fluoro-benzylsulfamoyl)-phenyl]-carbamicacid phenyl ester (256.7 mg, 0.64 mmol) in ACN (40 mL) was added C-(1h-pyrazol-4-yl)-methylamine (124.31 mg, 1.28 mmol) and TEA (129.54 mg,1.28 mmol). The reaction mixture was stirred at 80° C. overnight. Themixture was concentrated in vacuum. The residue was purified byprep-HPLC to giveN-(3-fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide(11 mg, yield 4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.60(s, 1H), 8.04 (t, J=6.4 Hz, 1H), 7.64 (d, J=9.2 Hz, 2H), 7.60-7.49 (m,4H), 7.37-7.28 (m, 1H), 7.12-7.00 (m, 3H), 6.93 (t, J=4.8 Hz, 1H), 4.16(d, J=4.8 Hz, 2H), 3.95 (d, J=6.4 Hz, 2H). MS: m/z 403.9 (M+H⁺).

Example 600: Synthesis ofN-(4-Methyl-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide

The title compound was prepared using general procedure ofN-(3-Fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide.¹H NMR (400 MHz, CD₃OD): δ=7.68 (d, J=8.8 Hz, 2H), 7.60 (s, 2H), 7.53(d, J=8.8 Hz, 2H), 7.09-7.02 (m, 4H), 4.30 (s, 2H), 3.96 (s, 2H), 2.26(s, 3H). MS: m/z 400.0 (M+H⁺).

Example 601: Synthesis of1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: A solution of 6-methyl-1H-indazole (1.5 g, 11.4 mmoL), KOH (1.6g, 28.6 mmoL) and I₂ (5.77 g, 22.7 mmoL) in DMF (40 mL) was stirred atroom temperature for 4 hrs. The reaction mixture was poured into H₂O(200 mL) and extracted with EA (200 mL). The EA layer was washed withsaturated aqueous NaSO₃ (100 mL), H₂O (200 mL), brine (200 mL), driedover Na₂SO₄ and concentrated to give 3-iodo-6-methyl-1H-indazole (2.25g, yield: 78%) as a yellow solid.

Step 2: To a solution of 3-iodo-6-methyl-1H-indazole (2.25 g, 8.7 mmoL)in DMF (15 mL) was added NaH (420 mg, 10.5 mmoL) at 0° C. and themixture was stirred at room temperature for 40 min under N₂ atmosphere(balloon). Then MeI (0.65 mL, 10.4 mmoL) was added into the reactionmixture and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was poured into H₂O (100 mL) and extracted with EA (100mL). The EA layer was washed with H₂O (100 mL), brine (100 mL), driedover Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by silica flash column (9% EA in PE) to give3-iodo-1,6-dimethyl-1H-indazole (1.62 g, yield: 68%) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ=7.33 (d, J=8.4 Hz, 1H), 7.13 (s, 1H), 7.03(d, J=8.0 Hz, 1H), 4.05 (s, 3H), 2.51 (s, 3H). MS: m/z 273.2 (M+H⁺).

Step 3: A suspension of 3-iodo-1,6-dimethyl-1H-indazole (1.1 g, 4.04mmoL), HCl salt of 4-aminobenzeneboronic acid (0.84 g, 4.84 mmoL), K₂CO₃(1.4 g, 10.14 mmoL) and Pd(dppf)Cl₂ (296 mg, 0.4 mmoL) in dioxane/H₂O(15 mL/2 mL) was stirred at 80° C. for 19 hrs under N₂ atmosphere(balloon). The reaction mixture was poured into H₂O (200 mL) andextracted with EA (150 mL). The EA layer was washed with brine (150 mL),dried over Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by silica gel column (PE/EA=5/1) to give4-(1,6-dimethyl-1H-indazol-3-yl)-phenylamine (670 mg, yield: 48%) as ayellow solid. MS: m/z 238.4 (M+H⁺).

Step 4: To a solution of 4-(1,6-dimethyl-1H-indazol-3-yl)-phenylamine(670 mg, 2.8 mmoL) and TEA (1.2 mL, 8.3 mmoL) in DCM (8 mL) was addedchloro-formicaciphenylester (575 mg, 3.7 mmoL) at 0° C. and the mixturewas stirred at room temperature for 1 hr. The reaction mixture waspoured into H₂O (50 mL) and extracted with EA (50 mL). The EA layer waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated to drynessin vacuum. The residue was purified by silica flash column (21% EA inPE) to give [4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-carbamic acidphenyl ester (490 mg, yield: 49%) as a white solid. MS: m/z 358.5(M+H⁺).

Step 5: A solution of [4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-carbamicacid phenyl ester (100 mg, 0.28 mmoL), c-pyridin-4-yl-methylamine (45mg, 0.42 mmoL) and TEA (0.2 mL, 1.39 mmoL) in MeCN (4 mL) was stirred at80° C. for 3 hrs. H₂O (20 mL) was added into the mixture and theresulting solid was collected by filtration. Then the pad was dissolvedin DMSO/MeOH (0.5 mL/1 mL) and standing there overnight. Then themixture was filtered and the pad was rinsed with MeOH to give1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea(6.8 mg, yield: 7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.84(s, 1H), 8.51 (d, J=5.6 Hz, 2H), 7.91 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.31 (d, J=6.0 Hz, 2H),7.04 (d, J=8.4 Hz, 1H), 6.78 (t, J=5.6 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H),4.03 (s, 3H), 2.48 (s, 3H). MS: m/z 372.2 (M+H⁺).

Example 602: Synthesis of1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.64 (brs, 1H), 8.66 (dd, J=10.8, 4.4 Hz,1H), 7.92 (d, J=8.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 7.59-7.50 (m, 4H),7.43 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.43 (s, 1H), 4.17 (d, J=4.8 Hz,2H), 4.03 (s, 3H), 2.47 (s, 3H). MS: m/z 361.1 (M+H⁺).

Example 603: Synthesis of1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.72 (s, 1H), 8.30 (s, 1H), 7.92 (d, J=8.4Hz, 1H), 7.83 (d, J=4.8 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.43 (s, 1H),7.05-7.03 (m, 2H), 6.66 (t, J=5.6 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 4.03(s, 3H), 2.48 (s, 3H). MS: m/z 362.1 (M+H⁺).

Example 604: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.78 (s, 1H), 8.60-8.56 (m, 2H), 8.30 (s,1H), 7.90 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.28 (dd, J=8.4,4.4 Hz, 1H), 7.03 (s, 1H), 6.69 (t, J=5.6 Hz, 1H), 4.39 (d, J=6.0 Hz,2H), 4.10 (s, 3H). MS: m/z 349.0 (M+H⁺).

Example 605: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.92 (s, 1H), 8.60-8.56 (m, 2H), 8.52-8.51(m, 2H), 7.90 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.32-7.27 (m,3H), 6.83-6.80 (m, 1H), 4.36 (d, J=6.0 Hz, 2H), 4.10 (s, 3H). MS: m/z359.1 (M+H⁺).

Example 606: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.57 (brs, 1H), 8.62-8.56 (m, 3H), 7.89(d, J=8.4 Hz, 2H), 7.57-7.55 (m, 4H), 7.28 (dd, J=8.0, 4.8 Hz, 1H), 6.39(t, J=5.6 Hz, 1H), 4.17 (d, J=5.2 Hz, 2H), 4.10 (s, 3H). MS: m/z 348.1(M+H⁺).

Example 607: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.73 (s, 1H), 8.60 (dd, J=4.4, 1.2 Hz, 1H),8.35 (d, J=8.4 Hz, 2H), 8.29 (s, 1H), 8.16 (dd, J=8.8, 1.2 Hz, 1H), 7.53(d, J=8.8 Hz, 2H), 7.45 (dd, J=8.8, 4.4 Hz, 1H), 7.03 (s, 1H), 6.67 (t,J=5.6 Hz, 1H), 4.39 (d, J=6.0 Hz, 2H), 4.11 (s, 3H). MS: m/z 349.1(M+H⁺).

Example 608: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.87 (s, 1H), 8.60 (dd, J=4.4, 1.6 Hz, 1H),8.51 (d, J=4.8 Hz, 2H), 8.36 (d, J=8.8 Hz, 2H), 8.16 (dd, J=8.4, 0.8 Hz,1H), 7.55 (d, J=8.4 Hz, 2H), 7.45 (dd, J=8.4, 4.4 Hz, 1H), 7.31 (d,J=6.0 Hz, 2H), 6.79 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.11 (s,3H). MS: m/z 359.1 (M+H⁺).

Example 609: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1,6-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 8.61-8.57 (m, 2H), 8.35(d, J=8.4 Hz, 2H), 8.16 (dd, J=8.8, 1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 4H),7.45 (dd, J=8.8, 4.4 Hz, 1H), 6.37 (t, J=5.6 Hz, 1H), 4.17 (d, J=4.2 Hz,2H), 4.11 (s, 3H). MS: m/z 348.1 (M+H⁺).

Example 610: Synthesis of1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3-iodo-1H-indazole (2.4 g, 10.0 mmol) indioxane (30 mL) and H₂O (10 mL) was added 4-nitrophenylboronic acid (2.5g, 15.0 mmol) and K₂CO₃ (4.14 g, 30 mmol), Pd(dppf)Cl2 (731.7 mg, 1.0mmol), the mixture was stirred at 80° C. overnight. The reaction wasmonitored by TLC. After completion, the mixture was filtered, thefiltrate was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford3-(4-nitro-phenyl)-1H-indazole (1.69 g, yield: 70.7%) as a yellow solid.

Step 2: To a solution of 3-(4-nitro-phenyl)-1H-indazole (600 mg, 2.5mmol) in EtOH (35 mL) and H₂O (5 mL) was added NH₄Cl (671.29 mg, 12. 5mmol), iron powder (700.9 mg, 12.5 mmol). The reaction mixture wasstirred at 80° C. overnight. Iron powder was filtered off and thefiltrate was concentrated in vacuum to give a residue, which waspurified by flash to give 4-(1 h-indazol-3-yl)-phenylamine (465 mg,yield: 88.7%) as a Brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ=12.89 (s,1H), 7.97 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz,1H), 7.35 (t, J=6.8 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.69 (t, J=8.4 Hz,2H), 5.32 (s, 2H).

Step 3: To a solution of 4-(h-Indazol-3-yl)-phenylamine (465 mg, 2.2mmol) in DCM (30 mL) was added phenyl chloroformate (688.9 mg, 4.4 mmol)and TEA (455.2 mg, 4.4 mmol), the mixture was stirred at 0° C. for 1 hr.The reaction was monitored by TLC. After completion, the mixture wasconcentrated in vacuum to give a residue, which was purified by a silicagel column (PE/EA=3/1) to afford [4-(1 h-indazol-3-yl)-phenyl]-carbamicacid phenyl ester (625.3 mg, yield: 85.4%) as a white solid.

Step 4: To a solution of [4-(h-indazol-3-yl)-phenyl]-carbamic acidphenyl ester (200 mg, 0.61 mmol) in ACN (30 mL) was addedc-pyridin-4-yl-methylamine (197.89 mg, 1.83 mmol) and TEA (185.2 mg,1.83 mmol), the mixture was stirred at 80° C. for 3 hrs. The reactionwas monitored by LCMS. After completion, the mixture was concentrated invacuum to give a residue, the residue was purified by prep-HPLC to give1-[4-(h-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea (6.7 mg, yield:3.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=13.09 (s, 1H), 8.88(s, 1H), 8.52 (d, J=6.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4Hz, 2H), 7.60-7.51 (m, 3H), 7.38 (t, J=7.6 Hz, 1H), 7.31 (d, J=5.6 Hz,2H), 7.18 (t, J=7.6 Hz, 1H), 6.79 (t, J=6.0 Hz, 1H) 4.36 (d, J=6.0 Hz,2H). MS: m/z 344.0 (M+H⁺).

Example 611: Synthesis of1-[4-(1H-Indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹H NMR (400MHz, DMSO-d₆): δ=13.09 (s, 1H), 8.83 (s, 1H), 8.30 (s, 1H), 8.04 (d,J=8.0 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.8 Hz, 3H), 7.38 (t,J=6.8 Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 7.03 (s, 1H), 6.76 (t, J=6.0 Hz,1H), 4.39 (d, J=5.2 Hz, 2H). MS: m/z 334.0 (M+H⁺).

Example 612: Synthesis of1-[4-(1H-Indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹H NMR (400MHz, DMSO-d₆): δ=13.08 (s, 1H), 12.55 (s, 1H), 8.59 (s, 1H), 8.04 (d,J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.63-7.48 (m, 5H), 7.38 (t, J=6.8Hz, 1H), 7.17 (t, J=7.2 Hz, 1H), 6.38 (t, J=5.6 Hz, 1H), 4.17 (d, J=4.8Hz, 2H). MS: m/z 333.0 (M+H⁺).

Example 613: Synthesis of1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 3-iodo-1H-indazole (2.4 g, 10.0 mmol) indioxane (30 mL) and H₂O (10 mL) was added 4-nitrophenylboronic acid (2.5g, 15.0 mmol) and K₂CO₃ (4.14 g, 30 mmol), Pd(dppf)Cl₂ (731.7 mg, 1.0mmol), the mixture was stirred at 80° C. overnight. The reaction wasmonitored by TLC. After completion, the mixture was filtered, thefiltrate was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford3-(4-nitro-phenyl)-1H-indazole (1.69 g, yield: 70.7%) as a yellow solid.

Step 2: To a solution of 3-(4-nitro-phenyl)-1H-indazole (500 mg, 2.1mmol) in THF (20 mL) was added NaH (75.6 mg, 3.15 mmol), MeI (387.49 mg,2.73 mmol). The reaction mixture was stirred at 0° C., for 1 hr. Themixture was added MeOH and concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=3/1) to give1-methyl-3-(4-nitro-phenyl)-1H-indazole (408 mg, yield: 77.08%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.36 (d, J=9.2 Hz, 2H), 8.29(d, J=8.8 Hz, 2H), 8.19 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.53(t, J=7.6 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 4.18 (s, 3H).

Step 3: To a solution of 1-methyl-3-(4-nitro-phenyl)-1H-indazole (408mg, 1.6 mmol) in EtOH (25 mL) and H₂O (5 mL) was added NH₄Cl (430.59 mg,8.05 mmol), iron powder (449.59 mg, 8.0 mmol). The reaction mixture wasstirred at 80° C. overnight. Iron powder was filtered off and thefiltrate was concentrated in vacuum to give a residue, which waspurified by flash to give 4-(1-methyl-1H-indazol-3-yl)-phenylamine (360mg, yield: 100%) as a Brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.98 (d,J=8.0 Hz, 1H), 7.65-7.58 (m, 3H), 7.40 (t, J=7.2 Hz, 1H), 7.16 (t, J=7.6Hz, 1H), 6.68 (d, J=8.4 Hz, 2H), 5.31 (s, 2H), 4.04 (s, 3H).

Step 4: To a solution of 4-(1-methyl-1H-indazol-3-yl)-phenylamine (360mg, 1.6 mmol) in DCM (30 mL) was added phenyl chloroformate (501 mg, 3.2mmol) and TEA (328.8 mg, 3.2 mmol), the mixture was stirred at 0° C. for1 hr. The reaction was monitored by TLC. After completion, the mixturewas concentrated in vacuum to give a residue, which was purified by asilica gel column (PE/EA=3/1) to afford[4-(1-methyl-1H-indazol-3-yl)-phenyl]-carbamic acid phenyl ester (527mg, yield: 95.3%) as a white solid.

Step 5: To a solution of [4-(1-methyl-1H-indazol-3-yl)-phenyl]-carbamicacid phenyl ester (100 mg, 0.29 mmol) in ACN (30 mL) was addedc-pyridin-4-yl-methylamine (67.27 mg, 0.58 mmol) and TEA (58.09 mg, 0.58mmol), the mixture was stirred at 80° C. for 3 hrs. The reaction wasmonitored by LCMS. After completion, the mixture was concentrated invacuum to give a residue, the residue was purified by prep-HPLC to give1-[4-(1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea (50.2mg, yield: 51.8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=8.91(s, 1H), 8.51 (d, J=5.6 Hz, 2H), 8.05 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.4Hz, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (t, J=7.2Hz, 1H), 7.31 (d, J=6.0 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 6.82 (t, J=5.6Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 4.08 (s, 3H). MS: m/z 358.0 (M+H⁺).

Example 614: Synthesis of1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=8.76 (s, 1H), 8.31 (s, 1H), 8.05 (d, J=8.4 Hz,1H), 7.85 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.8 Hz,2H), 7.44 (t, J=7.2 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.03 (s, 1H), 6.68(t, J=6.0 Hz, 1H), 4.39 (d, J=5.6 Hz, 2H), 4.08 (s, 3H). MS: m/z 348.0(M+H⁺).

Example 615: Synthesis of1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea. ¹HNMR (400 MHz, DMSO-d₆): δ=12.65 (s, 1H), 8.59 (s, 1H), 8.04 (d, J=8.4Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.8Hz, 4H), 7.44 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 6.38 (t, J=5.2Hz, 1H), 4.17 (d, J=5.2 Hz, 2H), 4.08 (s, 3H). MS: m/z 347.1 (M+H⁺).

Example 616: Synthesis of1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 5-fluoro-1H-indazole (2.0 g, 14.0 mmol) in DMF(50 mL) was added I₂ (7.46 g, 28.0 mmol) and KOH (2.4 g, 42 mmol), themixture was stirred at room temperature for 0.5 hr. The reaction wasmonitored by TLC. After completion, the mixture was filtered, thefiltrate was concentrated in vacuum to give a residue, which waspurified by a silica gel column (PE/EA=3/1) to afford5-fluoro-3-iodo-1H-indazole (3.7 g, yield: 96.1%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ=13.64 (s, 1H), 7.63 (dd, J=4.8, 4.4 Hz, 1H),7.38-7.30 (m, 1H), 7.20 (dd, J=6.4, 2.4 Hz, 1H).

Step 2: To a solution of 5-fluoro-3-iodo-1H-indazole (2.0 g, 7.6 mmol)in dioxane (40 mL) and H₂O (10 mL) was added 4-nitrophenylboronic acid(1.89 g, 11.4 mmol) and K₂CO₃ (2.09 g, 15.2 mmol), Pd(dppf)Cl₂ (555.56mg, 0.76 mmol), the mixture was stirred at 80° C. overnight. Thereaction was monitored by TLC. After completion, the mixture wasfiltered, the filtrate was concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=3/1) to afford5-fluoro-3-(4-nitro-phenyl)-1H-indazole (1.87 g, yield: 95.4%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=14.06 (s, 1H), 8.41-8.28 (m,4H), 7.99 (dd, J=7.2, 2.0 Hz, 1H), 7.73 (dd, J=4.4, 4.8 Hz, 1H),7.41-7.33 (m, 1H)

Step 3: To a solution of 5-fluoro-3-(4-nitro-phenyl)-1H-indazole (1.6 g,6.0 mmol) in THF (20 mL) was added NaH (216 mg, 9.0 mmol), MeI (1.2 g,9.0 mmol). The reaction mixture was stirred at 0° C., for 1 hr. Themixture was added MeOH and concentrated in vacuum to give a residue,which was purified by a silica gel column (PE/EA=3/1) to give5-fluoro-1-methyl-3-(4-nitro-phenyl)-1H-indazole (1.1 g, yield: 65.4%)as a white solid.

Step 4: To a solution of5-fluoro-1-methyl-3-(4-nitro-phenyl)-1H-indazole (1.0 g, 3.7 mmol) inEtOH (45 mL) and H₂O (5 mL) was added NH₄Cl (980 mg, 18.5 mmol), ironpowder (1017 mg, 8.5 mmol). The reaction mixture was stirred at 80° C.overnight. Iron powder was filtered off and the filtrate wasconcentrated in vacuum to give a residue, which was purified by flash togive 4-(5-fluoro-1-methyl-1H-indazol-3-yl)-phenylamine (1.1 g,yield: >1) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.23 (dd,J=7.2, 2.4 Hz, 1H), 7.69-7.58 (m, 3H), 7.35-7.26 (m, 1H), 6.70 (d, J=8.0Hz, 2H), 5.29 (s, 2H), 5.31 (s, 2H), 4.05 (s, 3H).

Step 5: To a solution of4-(5-fluoro-1-methyl-1H-indazol-3-yl)-phenylamine (500 mg, 2.0 mmol) inDCM (30 mL) was added phenyl chloroformate (343 mg, 2.2 mmol) and TEA (1mL), the mixture was stirred at 0° C. for 1 hr. The reaction wasmonitored by TLC. After completion, the mixture was concentrated invacuum to give a residue, which was purified by a silica gel column(PE/EA=3/1) to afford[4-(5-fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-carbamic acid phenylester (800 mg, yield:>1) as a white solid.

Step 6: To a solution of[4-(5-fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-carbamic acid phenylester (100 mg, 0.28 mmol) in ACN (30 mL) was addedc-pyridin-4-yl-methylamine (29.8 mg, 0.28 mmol) and TEA (0.5 mL), themixture was stirred at 80° C. for 3 hrs. The reaction was monitored byLCMS. After completion, the mixture was concentrated in vacuum to give aresidue, the residue was purified by prep-HPLC to give1-[4-(5-fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea(41.0 mg, yield: 39.8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ=8.87 (s, 1H), 8.52 (d, J=5.6 Hz, 2H), 7.85-7.79 (m, 3H), 7.72 (dd,J=4.8, 4.0 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.48-7.30 (m, 3H), 6.79 (t,J=6.0 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H), 4.08 (s, 3H). MS: m/z 376.1(M+H⁺).

Example 617: Synthesis of1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.63 (s, 1H), 8.58 (s, 1H), 7.83-7.79 (m,3H), 7.72 (dd, J=4.8, 4.0 Hz, 1H), 7.53 (d, J=8.8 Hz, 4H), 7.37-7.32 (m,1H), 6.37 (t, J=6.0 Hz, 1H), 4.17 (d, J=5.6 Hz, 2H), 4.08 (s, 3H). MS:m/z 365.1 (M+H⁺).

Example 618: Synthesis of1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.73 (s, 1H), 8.29 (s, 1H), 7.86-7.77 (m,3H), 7.72 (dd, J=4.4, 4.8 Hz, 1H), 7.54 (d, J=9.2 Hz, 2H), 7.39-7.31 (m,1H), 7.03 (s, 1H), 6.66 (t, J=6.0 Hz, 1H), 4.40 (d, J=5.6 Hz, 2H), 4.08(s, 3H). MS: m/z 366.1 (M+H⁺).

Example 619: Synthesis of1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: A solution of 7-methyl-1H-indazole (2 g, 15.15 mmoL), KOH (2.12g, 37.88 mmoL) and I₂ (7.7 g, 30.3 mmoL) in DMF (40 mL) was stirred atroom temperature for 4 hrs. The reaction mixture was poured into H₂O(200 mL) and extracted with EA (200 mL). The EA layer was washed withsaturated NaSO₃ (100 mL), H₂O (200 mL), brine (200 mL), dried overNa₂SO₄ and concentrated to give 3-iodo-7-methyl-1H-indazole (3.6 g,yield: 92%) as a yellow solid.

Step 2: To a solution of 3-iodo-7-methyl-1H-indazole (3.6 g, 13.9 mmoL)in DMF (20 mL) was added NaH (670 mg, 16.68 mmoL) at 0° C. and themixture was stirred at room temperature for 40 mins under N₂ atmosphere(balloon). Then MeI (1.04 ml, 16.68 mmoL) was added into the reactionmixture and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was poured into H₂O (100 mL) and extracted with EA (100mL). The EA layer was washed with H₂O (100 mL), brine (100 mL), driedover Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by silica flash column (9% EA in PE) to give3-iodo-1,7-dimethyl-1H-indazole (2.663 g, yield: 70%) as a yellow solid.¹H NMR (400 MHz, CDCl₃): δ=7.28 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.2 Hz,1H), 7.06 (t, J=7.6 Hz, 1H), 4.32 (s, 3H), 2.74 (s, 3H). MS: m/z 273.1(M+H⁺).

Step 3: A suspension of 3-iodo-1,7-dimethyl-1H-indazole (2.633 g, 9.68mmoL), HCl salt of 4-aminobenzeneboronic acid (1.8 g, 10.65 mmoL), K₂CO₃(3.34 g, 24.2 mmoL) and Pd(dppf)Cl₂ (0.7 mg, 0.9 mmoL) in dioxane/H₂O(20 mL/4 mL) was stirred at 80° C. for 19 hrs under N₂ atmosphere(balloon). The reaction mixture was poured into H₂O (200 mL) andextracted with EA (150 mL). The EA layer was washed with brine (150 mL),dried over Na₂SO₄ and concentrated to dryness in vacuum. The residue waspurified by silica gel column (PE/EA=4/1) to give4-(1,7-dimethyl-1H-indazol-3-yl)-phenylamine (1.396 g, yield: 60.8%) asa yellow solid. ¹H NMR (300 MHz, CDCl₃): δ=7.80 (d, J=7.8 Hz, 1H), 7.72(d, J=8.1 Hz, 2H), 7.12-7.02 (m, 2H), 6.82 (d, J=8.1 Hz, 2H), 4.36 (s,3H), 3.82 (brs, 2H), 2.80 (s, 3H).

Step 4: To a solution of 4-(1,7-dimethyl-1H-indazol-3-yl)-phenylamine(1.39 mg, 5.86 mmoL) and TEA (2.5 mL, 17.595 mmoL) in DCM (10 mL) wasadded phenyl chloroformate (1.1 g, 7.038 mmoL) at 0° C. and the mixturewas stirred at room temperature for 1 hr. The reaction mixture waspoured into H₂O (50 mL) and extracted with EA (50 mL). The EA layer waswashed with brine (50 mL), dried over Na₂SO₄ and concentrated to drynessin vacuum. The residue was purified by silica flash column (21% EA inPE) to give [4-(1,7-dimethyl-1H-indazol-3-yl)-phenyl]-carbamic acidphenyl ester (1.71 mg, yield: 81%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ=7.88 (d, J=8.0 Hz, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.0Hz, 2H), 7.42-7.38 (m, 2H), 7.26-7.22 (m, 4H), 7.12-7.04 (m, 3H), 4.36(s, 3H), 2.79 (s, 3H).

Step 5: A solution of [4-(1,7-dimethyl-1H-indazol-3-yl)-phenyl]-carbamicacid phenyl ester (100 mg, 0.28 mmoL), c-pyridin-4-yl-methylamine (45mg, 0.42 mmoL) and TEA (0.2 mL, 1.39 mmoL) in MeCN (4 mL) was stirred at80° C. for 3 hrs. The reaction mixture was poured into H₂O (20 mL) andfiltered. The pad was suspended in DMSO/MeOH (0.5 mL/1 mL) and standingthere overnight. Then the mixture was filtered and rinsed with MeOH (5mL) to give1-[4-(1,7-dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea(68 mg, yield: 66%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ=8.86(s, 1H), 8.52-8.50 (d, J=6 Hz, 2H), 7.83-7.77 (q, 3H), 7.56-7.54 (t,2H), 7.32-7.30 (d, J=6 Hz, 2H), 7.12-7.07 (q, 2H), 6.78 (s, 1H),4.36-4.34 (d, J=6 Hz, 2H), 4.31 (s, 3H), 2.77 (s, 3H). MS: m/z 372.1(M+H⁺).

Example 620: Synthesis of1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (300 MHz, DMSO-d₆): δ=8.73 (s, 1H), 8.29 (s, 1H), 7.83-7.77 (m,3H), 7.53 (d, J=8.1 Hz, 2H), 7.13-7.12 (m, 1H), 7.05-7.02 (m, 2H), 6.66(t, J=1.8 Hz, 1H), 4.39 (t, J=3.0 Hz, 2H), 4.31 (s, 3H), 2.77 (s, 3H).MS: m/z 362.1 (M+H⁺).

Example 621: Synthesis of1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (300 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.77 (s, 1H), 8.32-8.28 (m,2H), 8.04-8.02 (m, 1H), 7.90-7.88 (m, 2H), 7.58-7.56 (m, 2H), 7.02 (s,1H), 7.68 (s, 1H), 4.39 (s, 2H), 4.21 (s, 3H). MS: m/z 349.1 (M+H⁺).

Example 622: Synthesis of1-(4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (300 MHz, DMSO-d₆): δ=9.19 (s, 1H), 8.91 (s, 1H), 8.52-8.50 (m,2H), 8.31-8.29 (m, 1H), 8.04-8.02 (m, 1H), 7.90-7.88 (m, 2H), 7.59-7.57(m, 2H), 7.32-7.30 (m, 2H), 6.80 (s, 1H), 4.35 (s, 2H), 4.20 (s, 3H).MS: m/z 359.1 (M+H⁺)

Example 633: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (300 MHz, DMSO-d₆): δ=12.62 (brs, 1H), 9.19 (s, 1H), 8.62 (s,1H), 8.32-8.29 (m, 1H), 8.06-8.03 (m, 1H), 7.90-7.86 (m, 2H), 7.58-7.53(m, 4H), 6.39 (s, 1H), 4.20 (s, 3H), 4.17 (s, 2H). MS: m/z 348.1 (M+H⁺)

Example 634: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃+CD₃OD): δ=7.78-7.75 (m, 3H), 7.66 (s, 2H), 7.58(s, 2H), 7.521 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 4.35 (s, 3H), 4.33 (s, 2H), 2.80 (s, 3H). MS: m/z 361.1 (M+H⁺).

Example 635: Synthesis of1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

To a solution of[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-carbamic acidphenyl ester (120 mg, 0.35 mmol) in ACN (10 mL) was added(1H-pyrazol-3-yl)methanamine (55.7 mg, 0.42 mmol) and TEA (85 mg, 0.84mmol). Then the mixture was stirred at 80° C. overnight. This reactionwas monitored by LC-MS. The reaction mixture was then diluted with H₂O(10 mL) and extracted with EA (10 mL×3). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and evaporated in vacuum. Theresidue was purified by pre-HPLC to give1-[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea(3.8 mg, 3.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=9.26 (d,J=0.8 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 7.91 (d, J=9.2 Hz, 2H), 7.61-7.56(m, 5H), 4.32 (s, 2H), 4.12 (s, 3H). MS: m/z 348.1 (M+H)⁺.

Example 636: Synthesis of1-[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

To a solution of[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-carbamic acidphenyl ester (120 mg, 0.35 mmol) in ACN (10 mL) was addedC-oxazol-5-yl-methylamine (56.5 mg, 0.42 mmol) and TEA (85 mg, 0.84mmol). Then, the mixture was stirred at 80° C. overnight. This reactionwas monitored by LC-MS. The reaction mixture was then diluted with H₂O(10 mL) and extracted with EA (10 mL×3). The combined organic layer wasdried over anhydrous Na₂SO₄, and evaporated in vacuum. The residue waspurified by pre-HPLC to give1-[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea(1.5 mg, 1.23%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=7.97 (s,1H), 7.07 (d, J=6.0 Hz, 1H), 6.86 (s, 1H), 6.63-6.60 (m, 2H), 6.32-6.26(m, 3H), 5.76 (s, 1H), 3.21 (s, 2H), 2.82 (s, 3H). MS: m/z 349.1 (M+H)⁺.

Example 637: Synthesis of1-[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

Step 1: To a solution of 1H-pyrazolo[4,3-c]pyridine (500 mg, 4.2 mmol)in DMF (10 mL) was added I₂ (1.6 g, 6.3 mmol) and KOH (705.6 mg, 12.6mmol). Then the mixture was stirred at room temperature overnight. Thisreaction was monitored by LC-MS. The reaction mixture was then dilutedwith NaHSO₃ (aq, 10 mL) and extracted with EA (10 mL×3). The combinedorganic layer was dried over anhydrous Na₂SO₄, and evaporated in vacuum.The residue was purified by silica gel column chromatography (PE/EA=4/1)to give 3-iodo-1H-pyrazolo[4,3-c]pyridine (660 mg, 64%) as white oil.

Step 2: To a solution of 3-iodo-1H-pyrazolo[4,3-c]pyridine (660 mg, 2.69mmol) in THF (10 mL) was added NaH (60%, 162 mg, 4.04 mmol) at 0° C. andthis mixture was stirred at 0° C. for 0.5 hr. Then CH₃I (573 mg, 4.04mmol) was added at 0° C. The reaction temperature was allowed to warm toroom temperature slowly and stirred overnight. This reaction wasmonitored by LC-MS. The reaction mixture was quenched with H₂O (10 mL)extracted with EA (10 mL×3). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and evaporated in vacuum. The residue waspurified by silica gel column chromatography (PE/EA=4/1) to give{3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine (221 mg, 31.7%) as whiteoil.

Step 3: To a solution of {3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridine(220 mg, 0.85 mmol) in a mixture of dioxane (10 mL) and H₂O (1 mL) wasadded K₂CO₃ (235 mg, 1.7 mmol), Pd(dppf)Cl₂ (62 mg, 0.08 mmol) andp-nitrophenylboronic acid (170 mg, 1.02 mmol). Then the mixture wasstirred at 80° C. overnight. This reaction was monitored by LC-MS. Thereaction mixture was then diluted with H₂O (10 mL) and extracted with EA(10 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and evaporated in vacuum. The residue was purificated by silicagel column chromatography to give1-methyl-3-(4-nitro-phenyl)-1H-pyrazolo[4,3-c]pyridine (197 mg, 91.2%)as yellow oil.

Step 4: To a solution of1-methyl-3-(4-nitro-phenyl)-1H-pyrazolo[4,3-c]pyridine (277 mg, 1.09mmol) in a mixture of EtOH (10 mL) and H₂O (1 mL) was added Fe (244 mg,4.36 mmol) and NH₄Cl (233 mg, 4.36 mmol). Then the mixture was stirredat 80° C. overnight. This reaction was monitored by TLC (PE/EA=1/4). Thereaction mixture was then diluted with H₂O (10 mL) and extracted with EA(10 mL×3). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and evaporated in vacuum. The residue was purified by silicagel chromatography column (PE/EA=1/4) to give4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenylamine (120 mg, 49.2%)as yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ=9.31 (s, 1H), 8.37 (d, J=6.0Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.63 (d, J=6.0 Hz, 1H), 6.70 (d, J=8.8Hz, 1H), 5.42 (s, 2H), 4.04 (t, J=7.6 Hz, 3H).

Step 5: To a solution of4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenylamine (120 mg, 0.54mmol) in DCM (10 mL) was added phenyl chloroformate (100.7 mg, 0.65mmol) and TEA (65.1 mg, 0.65 mmol). Then the mixture was stirred at roomtemperature overnight. This reaction was monitored by LC-MS. The solventwas removed by vacuo. The residue was purificated by silica gel columnchromatography (PE/EA=4/1) to give[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-carbamic acidphenyl ester (152 mg, 82%) as yellow oil which was used to the next stepwithout further purification.

Step 6: To a solution of[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-carbamic acidphenyl ester (120 mg, 0.35 mmol) in ACN (5 mL) was added4-pyridinemethanamine (45.2 mg, 0.42 mmol) and TEA (70.8 mg, 0.7 mmol).Then the mixture was stirred at 80° C. for 3 hrs. This reaction wasmonitored by LC-MS. The reaction mixture was then diluted with H₂O (10mL) and extracted with EA (10 mL×3). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and evaporated in vacuum. Theresidue was purified by pre-HPLC to give1-[4-(1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea(25 mg, 20%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ=9.25 (s, 1H),8.48 (dd, J=8.8 Hz, J=1.6 Hz, 2H), 8.35 (d, J=6.0 Hz, 1H), 7.90 (dd,J=6.8 Hz, J=1.6 Hz, 2H), 7.60-7.57 (m, 3H), 7.42 (d, J=6.4 Hz, 2H), 4.48(s, 2H), 4.11 (s, 3H). MS: m/z 359.1 (M+H)⁺.

Example 638: Synthesis of1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

Step 1: To a solution of 1,5-dimethyl-1H-indazole (1 g, 7.58 mmol) andiodomethane (1.2 g, 8.33 mmol) in THF was added NaH (365 mg, 15.2 mmol)at 0° C. Then the reaction was stirred at room temperature for 2 hrs.The mixture was poured into H₂O (20 mL) and the aqueous phase wasextracted with EA (20 mL). The organic layer was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel column (PE/EA=4/1) to give1,5-dimethyl-1H-indazole (490 mg, yield: 44%) as a white solid.

Step 2: To a solution of 1,5-dimethyl-1H-indazole (490 mg, 3.36 mmol) inACN (15 mL) was added NBS (720 mg, 4.0 mmol). The reaction was stirredat room temperature for 2 hrs. The mixture was poured into sat.NaHCO₃solution (10 mL) and the aqueous phase was extracted with EA (10 mL).The organic layer was washed with brine (15 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gel column(PE/EA=4/1) to give 3-bromo-1,5-dimethyl-1H-indazole (840 mg, crude) asyellow oil.

Step 3 to 5: The title compound was prepared using general procedure of1-(4-(5-benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea. ¹H NMR(400 MHz, CDCl₃): δ=8.38 (d, J=6.0 Hz, 2H), 7.85 (s, 1H), 7.70 (d, J=8.4Hz, 2H), 7.64 (s, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.26-7.22 (m, 2H), 7.09(d, J=6.0 Hz, 2H), 6.08 (t, J=6.0 Hz, 1H), 4.31 (d, J=6.0 Hz, 2H), 4.01(s, 3H), 2.43 (s, 3H). MS: m/z 372.1 (M+H⁺).

Example 639: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=12.61 (s, 1H), 8.56 (s, 1H), 7.83-7.81 (m,3H), 7.55-7.51 (m, 5H), 7.27 (d, J=8.8 Hz, 1H), 6.35 (t, J=5.6 Hz, 1H),4.18 (d, J=5.2 Hz, 2H), 4.04 (s, 3H), 2.45 (s, 3H). MS: m/z 361.1(M+H⁺).

Example 640: Synthesis of1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃): δ=7.91 (d, J=8.4 Hz, 2H), 7.82 (s, 1H), 7.73(s, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.32 (s, 1H), 7.27 (s, 1H), 7.01 (s,1H), 6.58 (s, 1H), 5.19 (s, 1H), 4.53 (s, 2H), 4.08 (s, 3H), 2.49 (s,3H). MS: m/z 362.1 (M+H⁺).

Example 641: Synthesis of1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃+CD₃OD): δ=7.93 (d, J=2.4 Hz, 2H), 7.79 (d, J=8.4Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (s, 1H), 7.39 (s, 2H), 7.02 (s,1H), 4.51 (s, 2H), 4.21 (s, 3H). MS: m/z 382.0 (M+H⁺).

Example 642: Synthesis of1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃): δ=8.42 (d, J=4.8 Hz, 2H), 7.76 (s, 2H), 7.72(d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.30-7.25 (m, 2H), 7.12 (d,J=5.6 Hz, 2H), 6.04 (t, J=5.6 Hz, 1H), 4.33 (d, J=6.0 Hz, 2H), 4.02 (s,3H). MS: m/z 392.1 (M+H⁺).

Example 643: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-chloro-1-methyl-1H-indazol-3-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, DMSO-d₆): δ=8.59 (s, 1H), 8.07 (s, 1H), 7.83 (d, J=8.8Hz, 2H), 7.73 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 3H), 7.46 (d, J=8.4Hz, 1H), 6.37 (t, J=5.2 Hz, 1H), 4.18 (d, J=5.2 Hz, 2H), 4.08 (s, 3H).MS: m/z 381.1 (M+H⁺).

Example 644: Synthesis of1-(4-(1,4-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃+CD₃OD): δ=8.66 (s, 1H), 8.29 (s, 1H), 8.11 (s,1H), 7.48 (d, J=4.8 Hz, 3H), 7.25-7.22 (m, 3H), 7.02 (s, 1H), 6.64 (t,J=5.6 Hz, 1H), 4.40 (d, J=6.0 Hz, 1H), 4.04 (s, 3H), 2.50 (d, J=1.6 Hz,3H). MS: m/z 362.1 (M+H⁺).

Example 645: Synthesis of1-(4-(1,4-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CD₃OD): δ=8.49 (d, J=4.8 Hz, 2H), 8.06 (s, 1H),7.46-7.37 (m, 5H), 7.31-7.24 (m, 3H), 4.48 (s, 2H), 4.06 (s, 3H), 2.49(s, 3H). MS: m/z 372.1 (M+H⁺).

Example 646: Synthesis of1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,4-dimethyl-1H-indazol-3-yl)phenyl)urea

The title compound was prepared using general procedure of1-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea.¹H NMR (400 MHz, CDCl₃+CD₃OD): δ=8.05 (s, 1H), 7.60 (d, J=12.4 Hz, 3H),7.48 (d, J=8.4 Hz, 2H), 7.34 (s, 2H), 7.29 (d, J=8.8 Hz, 1H), 4.36 (s,2H), 4.11 (s, 3H), 2.54 (s, 3H). MS: m/z 361.1 (M+H⁺).

Example 647: Synthesis of1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea

The title compound was prepared using general procedure of1-[4-(5-methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (300 MHz, DMSO-d₆): δ=8.89 (s, 1H), 8.51 (d, J=3.9 Hz, 2H), 7.82(d, J=7.8 Hz, 2H), 7.58-7.54 (m, 3H), 7.36-7.31 (m, 3H), 7.09 (d, J=9.0Hz, 1H), 6.82 (t, J=5.7 Hz, 1H), 4.36 (d, J=5.4 Hz, 2H), 4.04 (s, 3H),3.84 (s, 3H). MS: m/z 388.1 (M+H⁺).

Example 648: Synthesis of1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea

The title compound was prepared using general procedure of1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea.¹H NMR (300 MHz, DMSO-d₆): δ=12.63 (brs, 1H), 8.57 (s, 1H), 7.81 (d,J=8.4 Hz, 2H), 7.60-7.50 (m, 5H), 7.36 (s, 1H), 7.09 (d, J=8.7 Hz, 1H),6.37 (t, J=5.4 Hz, 1H), 4.17 (d, J=5.1 Hz, 2H), 4.04 (s, 3H), 3.84 (s,3H). MS: m/z 377.1 (M+H⁺).

Example 649: Synthesis of1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea

Step 1: To a solution of 1H-Indazol-5-ol (1.3 g, 10 mmol) in DMF (40 mL)was added K₂CO₃ (3.5 g, 25 mmol) and CH₃I (1.6 mL, 25 mmol) at roomtemperature, the resulting mixture was stirred at 120° C. for 18 hrs.After cooled to room temperature, the reaction was acidified with theaddition of saturated aqueous NH₄Cl (10 ml). The solvent was removedunder vacuum and the residue was diluted with water (200 mL). Theaqueous phase was extracted with EA (50 mL×3). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated todryness under reduced pressure. The residue was purified by silica gelcolumn (PE/EA=4/1) to give 5-methoxy-1-methyl-1H-indazole (876 mg,yield: 54%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ=7.87 (s, 1H),7.28 (d, J=7.2 Hz, 1H), 7.08-7.05 (m, 2H), 4.04 (s, 3H), 3.84 (s, 3H).MS: m/z 163.0 (M+H⁺).

Step 2: To a solution of 5-methoxy-1-methyl-1H-indazole (476 mg, 2.9mmol) in DMF (10 mL) was added KOH (195 mg, 3.5 mmol) and I₂ (889 mg,3.5 mmol). The resultant mixture was stirred at 80° C. overnight. Thereaction was quenched with the addition of saturated aqueous NaHSO₃ (100mL). The mixture was extracted with EA (30 mL×3). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated todryness under reduced pressure. The residue was purified by silica gelcolumn (PE/EA=8/1) to give 3-iodo-5-methoxy-1-methyl-1H-indazole (580mg, yield: 69%) as a white solid.

Step 3: To a mixture of 3-iodo-5-methoxy-1-methyl-1H-indazole (540 mg,1.88 mmol) and 4-aminophenylboronic acid (HCl salt, 461 mg, 2.7 mmol) indioxane/H₂O (5 mL/5 mL) was added PdCl₂(dppf) (69 mg, 0.09 mmol) andNa₂CO₃ (942 mg, 7.6 mmol). The resultant mixture was degassed andbackfilled with N2 for three times. The it was stirred at 100° C.overnight. After cooled to room temperature, the reaction solution waspoured into H₂O (50 mL). The mixture was extracted with EA (30 mL×3).The combined organic layer was dried over anhydrous NaSO₄, filtered andconcentrated to dryness under reduced pressure. The residue was purifiedby silica gel column (DCM/EA) to give4-(5-methoxy-1-methyl-1H-indazol-3-yl)-phenylamine (370 mg, yield: 78%)as a tan solid. ¹H NMR (300 MHz, CDCl₃): δ=7.72 (d, J=8.1 Hz, 2H),7.32-7.26 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.83 (d, J=7.5 Hz, 2H), 4.07(s, 3H), 3.88 (s, 3H), 3.79 (brs, 2H). MS: m/z 254.4 (M+H⁺).

Steps 4 and 5: A solution of triphosgen (54 mg, 0.18 mmol) in THF (5 mL)was added to a mixture of4-(5-methoxy-1-methyl-1H-indazol-3-yl)-phenylamine (127 mg, 0.5 mmol)and Et₃N (0.17 mL, 1.25 mmol) in THF (10 mL) dropwise, the mixture wasstirred at room temperature for 0.5 hr. The reactant was filtered andconcentrated to dryness. MeCN (20 mL) was added, followed by3-oxazol-5-yl-methylamine (60 mg, 0.6 mmol) and Et₃N (0.17 mL, 1.25mmol). The mixture was stirred at 80° C. for 2 hrs. The reactionsolution was concentrated and the residue was purified by silica gelcolumn (DCM/MeOH=15/1) to give1-[4-(5-methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea(130 mg, yield: 69%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ=8.72(s, 1H), 8.30 (s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.60-7.50 (m, 3H), 7.36(s, 1H), 7.09 (d, J=9.6 Hz, 1H), 7.03 (s, 1H), 6.67 (t, J=6.3 Hz, 1H),4.39 (d, J=6.3 Hz, 2H), 4.04 (s, 3H), 3.84 (s, 3H). MS: m/z 378.1(M+H⁺).

Pharmaceutical Compositions Example A-1: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I), (Ia), (II), (Ia), (III), (IIIa), (IV), (IVa),(V) or (Va), or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof, is dissolved in 2% HPMC, 1% Tween 80 in DI water,pH 2.2 with MSA, q.s. to at least 20 mg/mL. The mixture is incorporatedinto a dosage unit form suitable for administration by injection.

Example A-2: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa),(V) or (Va), or pharmaceutically acceptable salt, N-oxide, racemate orstereoisomer thereof, is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

BIOLOGY EXAMPLES Example B-1: Enzyme Assay and NMN Detection

NAMPT reaction was performed in 50 mM HEPES, pH 7.5, containing 5 mMMgCl₂, 0.1% Prionex, 0.005% Tween 20, and 1 mM TCEP at room temperaturein Greiner 384-well black polypropylene plates. The concentration ofsubstrates and enzymes in the final assay were as follows: ATP (120 uM),nicotinamide (5 uM), phosphoribosylpyrophosphate (6.25 uM), NAMPT enzyme(16 nM), pyrophosphatase (0.04 U/ml) in the final reaction volume 6 uL.Following 2 h incubation the reaction was stopped by addition 2.5 ul 20%acetophenone in dimethyl sulfoxide (DMSO) and 2.5 ul 2 MKOH. Plates werecentrifuges and added with 10.5 ul 88% formic acid. The fluorescence(ex380/em460) was measured following another short incubation and 30 minincubation. The increased concentration of NMN was determined from acalibration curve obtained at the time of experiment.

Representative data for exemplary compounds disclosed in Table 1 ispresented in the following table B-1.

TABLE B-1 Compound EC₅₀ Ethyl4-(3-((1H-pyrazol-4-yl)methyl)ureido)benzoate B Ethyl4-(3-(oxazol-4-ylmethyl)ureido)benzoate E Ethyl4-(3-((3,5-dimethylisoxazol-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((1-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate EN-(3-Chloro-phenyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzamide B4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-methoxyphenyl)benzamide B4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-chlorophenyl)benzamide B4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-methoxyphenyl)benzamide B4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-chlorophenyl)benzamide B4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-methoxyphenyl)benzamide BEthyl 4-(3-(oxazol-5-ylmethyl)ureido)benzoate D Ethyl4-(3-((3-amino-1H-pyrazol-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((1H-imidazol-5-yl)methyl)ureido)benzoate E Ethyl4-(3-((1-methyl-1H-pyrazol-5-yl)methyl)ureido)benzoate E Ethyl4-(3-((1H-imidazol-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((1H-pyrazol-3-yl)methyl)ureido)benzoate E Ethyl4-(3-((3-methyl-1H-pyrazol-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)ureido)benzoateE Ethyl 4-(3-((1H-1,2,3-triazol-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((1-methyl-1H-imidazol-5-yl)methyl)ureido)benzoate E Ethyl4-(3-((1-methyl-1H-imidazol-4-yl)methyl)ureido)benzoate E4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-N-pyridin-2-yl-benzenesulfonamide CN-Benzyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide B1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-B ureaN-Cyclobutylmethyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideB N-Phenyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide BN-Cyclopentyl-N-methyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideB N-Benzyl-N-isopropyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamideAN-Benzyl-N-isopropyl-4-(3-thiazol-5-ylmethyl-ureido)-benzenesulfonamideAN-Benzyl-N-isopropyl-4-(3-thiazol-2-ylmethyl-ureido)-benzenesulfonamideEN-Benzyl-N-isopropyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideA1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-ureaBN-(3-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideBN-(2-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideAN-(2-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideAN-(4-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideAN-(4-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideB N-Benzyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamide B1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-thiazol-5-ylmethyl-ureaB1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(3,5-dimethyl-isoxazol-4-E ylmethyl)-urea1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea A1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea A1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea A1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA 1-(4-Benzenesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea A1-(4-Benzenesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea A1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA N-[4-(3-Oxazol-5-ylmethyl-ureido)-phenyl]-benzenesulfonamide BN-Oxazol-5-ylmethyl-2-(4-phenylmethanesulfonylamino-cyclohexa-1,5-dienyl)-acetamideB N-{4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-phenyl}-benzenesulfonamide AN-(4-(3-((1H-pyrazol-4-yl)methyl)ureido)phenyl)-1-phenylmethanesulfonamideA N-(4-{3-[1-(4-Methoxy-benzyl)-1H-pyrazol-4-ylmethyl]-ureido}-phenyl)-E benzenesulfonamide Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D =5-20 uM; E = >20 uM

Representative data for exemplary compounds disclosed in Table 2 ispresented in the following table B-2.

TABLE B-2 Compound EC₅₀ 1-(4-Fluorophenyl)-3-(pyridin-4-ylmethyl)urea E1-(4-Chlorophenyl)-3-(pyridin-4-ylmethyl)urea D1-(Pyridin-4-ylmethyl)-3-(p-tolyl)urea E Ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate E Ethyl3-(3-(pyridin-4-ylmethyl)ureido)benzoate D1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea D1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea E1-(4-Methoxyphenyl)-3-(pyridin-4-ylmethyl)urea EN,N-diethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide E4-(3-(Pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide CN-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide DN-phenyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide CN-ethyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-methyl-N-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-(2-hydroxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-butyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-cyclopentyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide D Ethyl4-(3-(pyridin-4-ylmethyl)ureido)benzoate C Ethyl4-(3-((2-aminopyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((2-methoxypyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((3-methylpyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((3-aminopyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((2-methylpyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((2-chloropyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((3-chloropyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((2-fluoropyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-((3-fluoropyridm-4-yl)methyl)ureido)benzoate B4-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid E3-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid E4-(3-(Pyridin-4-ylmethyl)ureido)benzamide DN-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide CN-Isopropyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN,N-dimethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(2-morpholinoethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-cyclohexyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide CN-(2-(piperidin-1-yl)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide C4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide CN-isobutyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-cyclobutyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-(cyclopropylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide C4-(3-(pyridin-4-ylmethyl)ureido)-N-(tetrahydrofuran-3-yl)benzamide DN-(2-methoxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide CN-phenethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide B1-(4-(Morpholine-4-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea D1-(4-(4-Methylpiperazine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea D1-(4-(Piperidine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea D1-(Pyridin-4-ylmethyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea DN-(cyclopentylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide D1-(4-(8-Oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaB N-(pyridin-4-ylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(4-methylphenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-fluorophenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3-ethoxypropyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(2-(dimethylamino)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-(2-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(3-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(3-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide CN-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(2-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(3-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide B1-(4-(Isoindoline-2-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea E1-(Pyridin-4-ylmethyl)-3-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)ureaB N-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(2-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(2-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide B4-(3-(Pyridin-4-ylmethyl)ureido)-N-(o-tolyl)benzamide B4-(3-(Pyridin-4-ylmethyl)ureido)-N-(m-tolyl)benzamide BN-(4-(methoxymethyl)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide EN-(2-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(2-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide B4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(trifluoromethoxy)phenyl)benzamideB4-(3-(pyridin-4-ylmethyl)ureido)-N-(3-(trifluoromethoxy)phenyl)benzamideC4-(3-(pyridin-4-ylmethyl)ureido)-N-(4-(trifluoromethoxy)phenyl)benzamideB N-(4-ethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(4-isopropoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BMethyl 4-(4-(3-(pyridin-4-ylmethyl)ureido)benzamido)benzoate BN-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3,4-dimethylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(3,4-dimethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(benzo[d][1,3]dioxol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-(4-methoxy-3-methylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide BN-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamideB N-(pyridin-2-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide DN-(pyridin-3-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide E4-(3-(pyridin-4-ylmethyl)ureido)-N-(pyrimidin-5-yl)benzamide BN-(3-methylisoxazol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide C4-(3-(Pyridin-4-ylmethyl)ureido)-N-(thiophen-2-yl)benzamide CN-Cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide DN-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide CN-Propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-Isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-Cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide CN-Cyclobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-cyclopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide B4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrrolidin-3-yl-benzenesulfonamide DN-(1-Methyl-pyrrolidin-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideC N-(tert-butyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(2-Dimethylamino-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-Cyclopropylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-Cyclobutylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-pyrrolidin-1-yl-ethyl)-benzensulfonamideC N-[2-(4-Methyl-piperazin-1-yl)-ethyl]-4-(3-pyridin-4-ylmethyl-ureido)-B benzenesulfonamideN-(2-Morpholin-4-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(2-Piperidin-1-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideC N-(2-Hydroxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideC4-(3-Pyridin-4-ylmethyl-ureido)-N-(tetrahydro-furan-3-yl)-benzenesulfonamideB N-(2-Methoxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(3-Methoxy-propyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(1-Ethyl-pyrrolidin-2-ylmethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-neopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-(1-Cyclobutyl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(2-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide AN-(3-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-(3-Methoxy-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamideB N-(2-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(3-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamideB N-(2-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(3-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(4-cyanobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide B2-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl A ester3-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl B ester4-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl B ester4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-benzenesulfonamideA4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethoxy-benzyl)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethoxy-benzyl)-benzenesulfonamideBN-(2-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideAN-(3-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(4-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(4-Methanesulfonyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N,N-dimethyl-4-((4-(3-(pyridin-4- Bylmethyl)ureido)phenylsulfonamido)methyl)benzenesulfonamideN-(4-((dimethylamino)methyl)benzyl)-4-(3-(pyridin-4- Aylmethyl)ureido)benzenesulfonamideN-(4-Methoxymethyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-(1-phenylethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide BN-Pyridin-4-ylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB4-(3-Pyridin-4-ylmethyl-ureido)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-A benzenesulfonamideN,N-Dimethyl-4-(3-pyridin-4-ylmethy-ureido)-benzenesulfonamide CN,N-Diethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-(2-Hydroxy-ethyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-Cyclopentyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide AN-(2-Fluoro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideAN-(2-Chloro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideA 1-[4-(Piperazine-1-sulfonyl)-phenyl}-3-pyridin-4-ylmethyl-urea DN-Cyclobutylmethyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-Cyclohexyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-Cyclopentyl-N-isobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideAN-Cyclopentyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideA N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(2- A(trifluoromethyl)benzyl)benzenesulfonamideN-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-A benzenesulfonamideN-(2-Methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideAN-Benzyl-N-isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideA N-Benzyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide AN-Benzyl-N-cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideA N-Benzyl-N-propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide AN,N-Dibenzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide EN-Methyl-N-(2-methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideAN-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamideA N-Benzyl-N-phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BPyridin-4-ylmethyl-3-[4-(pyrrolidine-1-sulfonyl)-phenyl]-urea B1-[4-(Piperidine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(Morpholine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(8-Chloro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-A ureaPyridin-4-ylmethyl-3-[4-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-B phenyl]-ureaPyridin-4-ylmethyl-3-[4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-B phenyl]-urea1-[4-(8-Fluoro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-A urea1-[4-(8-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-A urea1-[4-(3-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-B urea N-Phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide BN-(2-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(3-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideBN-(4-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB 4-(3-Pyridin-4-ylmethyl-ureido)-N-o-tolyl-benzenesulfonamide B4-(3-Pyridin-4-ylmethyl-ureido)-N-m-tolyl-benzenesulfonamide B4-(3-Pyridin-4-ylmethyl-ureido)-N-p-tolyl-benzenesulfonamide B4-(3-Pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide BN-(4,5-Dimethyl-oxazol-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideEN-(5-Methyl-isoxazol-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideE 4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrimidin-2-yl-benzenesulfonamide DN-(4-Methyl-pyrimidin-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamideB N-Pyridin-2-yl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide EN-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide EN-benzyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide D1-(3-(morpholinosulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea EN-(cyclobutylmethyl)-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamideE N-phenethyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide E4-(3-pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide B4-(3-pyridin-4-ylmethyl-ureido)-N-(3-chloro-phenyl)-benzenesulfonamide B4-(3-pyridin-4-ylmethyl-ureido)-N-(4-chloro-phenyl)-benzenesulfonamide B1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-(4-Benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea A1-(4-Phenylmethanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea C1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea BN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide A2-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideB3-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideA4-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideB 2-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideA 3-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideA 4-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideA N-[4-(3-Benzyl-ureido)-phenyl]-C-phenyl-methanesulfonamide A1-(2-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamideA1-(3-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamideA1-(4-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamideAN-Methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAN-Isopropyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideC N-Methyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamideBN-Isopropyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideC N-Phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideBN-Methyl-N-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideB Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D = 5-20 uM; E = >20uM

Representative data for exemplary compounds disclosed in Table 3 ispresented in the following table B-3.

TABLE B-3 Compound Name EC₅₀1-(4-Chlorophenyl)-3-(pyridin-3-ylmethyl)urea E1-(4-Fluorophenyl)-3-(pyridin-2-ylmethyl)urea E1-(4-Chlorophenyl)-3-(pyridin-2-ylmethyl)urea E1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea E1-(Pyridin-2-ylmethyl)-3-(p-tolyl)urea E1-(4-Fluorophenyl)-3-(pyridin-3-ylmethyl)urea E1-(Pyridin-3-ylmethyl)-3-(p-tolyl)urea E1-(Pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea E1-(4-Methoxyphenyl)-3-(pyridin-3-ylmethyl)urea E1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea E1-(Pyridin-2-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea E1-(4-Methoxyphenyl)-3-(pyridin-2-ylmethyl)urea E Ethyl4-(3-(pyridin-2-ylmethyl)ureido)benzoate E Ethyl4-(3-(pyridin-3-ylmethyl)ureido)benzoate E Ethyl4-(3-(pyridin-4-ylmethyl)thioureido)benzoate E Ethyl4-(3-benzylureido)benzoate E Ethyl4-(3-(pyrimidin-5-ylmethyl)ureido)benzoate E Ethyl4-(3-((1,2,3,4-tetrahydroquinolin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-(quinolin-4-ylmethyl)ureido)benzoate E Ethyl4-(3-((3-chloropyridin-4-yl)methyl)ureido)benzoate E Ethyl4-(3-(pyridazin-4-ylmethyl)ureido)benzoate E 3-(3-Benzyl-ureido)-benzoicacid E Methyl 4-(1-methyl-3-(pyridin-4-ylmethyl)ureido)benzoate EN-Benzyl-4-(3-benzyl-ureido)-benzenesulfonamide E1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-3-ylmethyl-ureaE1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-2-ylmethyl-ureaE Ethyl 6-(3-(pyridin-4-ylmethyl)ureido)nicotinate E Ethyl5-(3-(pyridin-4-ylmethyl)ureido)picolinate E6-(3-Pyridin-4-ylmethyl-ureido)-nicotinamide E5-(3-(pyridin-4-ylmethyl)ureido)picolinamide C4-(3-Benzyl-3-methyl-ureido)-benzoic acid ethyl ester E1-[(Pyridin-4-ylmethyl)-carbamoyl]-1H-indazole-5-carboxylic acid ethylester E 4-(2-Oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoic acidethyl ester E 4-(2-oxo-3-pyridin-4-ylmethyl-imidazolidin-1-yl)-benzoicacid E Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D = 5-20 uM; E= >20 uM

Representative data for exemplary compounds disclosed in Table 4 ispresented in the following table B-4.

TABLE B-4 Compound Name EC₅₀1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaB 1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-2-ylsulfonyl)phenyl)urea B1-[4-(5-Methyl-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB 1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)ureaA 1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-fluorophenyl)sulfonyl)phenyl)ureaA 1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-fluorophenyl)sulfonyl)phenyl)ureaA1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaA 1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea B1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaB 1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-4-sulfonyl)-phenyl]-urea B1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-3-sulfonyl)-phenyl]-urea B1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-2-sulfonyl)-phenyl]-urea A1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea B1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA C-(3-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}- AmethanesulfonamideC-(2-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}- AmethanesulfonamideC-(4-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}- Amethanesulfonamide1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-ureaBC-(3,4-Dichloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-A methanesulfonamideN-(3-Fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideB1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB 1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyrimidin-5-ylsulfonyl)phenyl)urea B1-(4-Cyclohexanesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea B1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA1-(1H-Pyrazol-4-ylmethyl)-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB 1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea C1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaDN-(4-Methyl-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamideB1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB 1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea B1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea B1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA 1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea B1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaC1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaC1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaC of1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB 1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea C1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-B phenyl}-urea1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-yl)phenyl)urea D1-[4-(1H-Indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea B1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea B1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)ureaB 1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-benzylthiazol-2-yl)phenyl)urea C1-((1H-Pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-ylamino)phenyl)ureaE1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-ureaB1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-m-tolyl-thiazol-2-ylamino)-phenyl]-ureaB1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-p-tolyl-thiazol-2-ylamino)-phenyl]-ureaC1-{4-[4-(2-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)ureaB1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-{4-[4-(3-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaB1-{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(3-methoxyphenyl)thiazol-2-yl)amino)phenyl)ureaB 1-(4-Benzothiazol-4-yl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea B1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)ureaC1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-{4-[4-(2-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaD1-{4-[4-(3-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaC1-{4-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(4-methoxyphenyl)thiazol-2-yl)amino)phenyl)ureaB 1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea E1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-3-ylsulfonyl)phenyl)ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)ureaA1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-chloro-1-methyl-1H-indazol-3-yl)phenyl)ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)ureaB 1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea D1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)ureaC1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,4-dimethyl-1H-indazol-3-yl)phenyl)ureaB1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaC1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-3-yl-benzenesulfonyl)-phenyl]-ureaB 1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea A1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaA1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaD1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaC1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-ureaB1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaD1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaB1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-ureaD1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-chloro-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)ureaB1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)ureaD1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-(6-methoxypyridin-3-yl)phenyl)sulfonyl)phenyl)ureaD1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)ureaD1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-methyl-[1,l′-biphenyl]-2-yl)sulfonyl)phenyl)ureaB Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D = 5-20 uM; E = >20uM

Representative data for exemplary compounds disclosed in Table 5 ispresented in the following table B-5.

TABLE B-5 Compound Name EC₅₀1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaB 1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-(3-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamideA1-(4-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamideA1-(3,4-Dichlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamideA1-(2-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamideA 1-Oxazol-5-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea C1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-2-ylsulfonyl)phenyl)urea B1-(4-((3-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea A1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea B1-(4-((2-Methoxyphenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-Oxazol-5-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea B1-Oxazol-5-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea B1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea C1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-Oxazol-5-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-ureaB1-(Oxazol-5-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaB1-(Oxazol-5-ylmethyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaB 1-(4-Cyclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea C1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA 1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-(4-((4-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea B1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea C1-Oxazol-5-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA 1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea B1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea C1-Oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea B1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-ureaB 1-Oxazol-5-ylmethyl-3-[4-(pyrazine-2-sulfonyl)-phenyl]-urea B1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-ureaC 1-Oxazol-5-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea D1-Oxazol-5-ylmethyl-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-B urea 1-[4-(1H-Indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea D1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea C1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea C1-(Oxazol-5-ylmethyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea C1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea D1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-(4-(Benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea D1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea D1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea B1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea C1-(4-Benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea B1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-ureaE1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-ureaC 1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea E1-(4-([1,1′-Biphenyl]-3-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea B1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea A1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-ureaC1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)ureaB 1-(Oxazol-5-ylmethyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea B1-(Oxazol-5-ylmethyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea D1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-ureaC 1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea C1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-ureaD Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D = 5-20 uM; E = >20uM

Representative data for exemplary compounds disclosed in Table 6 ispresented in the following table B-6.

TABLE B-6 Compound Name EC₅₀C-(4-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAC-(4-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideA C-(4-Cyclopropyl-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]- AmethanesulfonamideC-Biphenyl-4-yl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAC-(4-Cyano-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideB 1-[4-(3-Bromo-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-urea AC-(2-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAC-(3-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-m-tolyl-methanesulfonamideAC-(3-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideAN-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p-tolyl-methanesulfonamideAC-(2-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideB 1-[4-(4-Fluoro-phenylmethanesulfonyl)-phenyl]-3-(1H-pyrazol-4-yl)-ureaB 1-[4-(2-Methyl-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-ureaAC-(2-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamideA1-Pyridin-4-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaB 1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-Pyridin-4-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea A1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-(4-(Pyridin-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(Pyridin-4-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea B1-Pyridin-4-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea B1-Pyridin-4-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea B1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea A1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-ureaB1-(Pyridin-4-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaA1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)ureaB 1-(4-Cyclohexanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea B1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA 1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB Pyridin-4-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea B1-Pyridin-4-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-ureaA 1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB of1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-Pyridin-4-ylmethyl)-3-(4-(thiazol-5-ylsulfonyl)phenyl)urea B1-[4-(Pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaC1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaC 1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaA 1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB 1-Pyridin-4-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea C1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-B phenyl}-urea1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea D1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea D1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-[4-(Benzothiazol-2-ylamino)-phenyl]-3-pyridin-4-ylmethyl-urea D1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(4-Benzothiazol-4-yl-phenyl)-3-pyridin-4-ylmethyl-urea B1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-ureaB 1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-pyridin-4-ylmethyl-urea E1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea A1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-ureaD1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)ureaC 1-(4-((5-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea D1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-(4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)-3-(pyridin-4-ylmethyl)ureaB 1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-(4-(1,4-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea B1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea A1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea B1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaD1-[4-(2-Pyridin-3-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-[4-(2-Pyridin-4-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB 1-[4-(4′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaD 1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB 1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaC1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-ureaD1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaD1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaD 1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-ureaB1-(4-((2′-Chloro-[1,l′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaB1-(4-((4′-Cyano-[1,l′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaD1-(4-((2-(6-Methoxypyridin-3-yl)phenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaD1-(4-((3′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaC1-(4-((2′-Methyl-[1,l′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaB1-(3-Cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)ureaB Where A = <100 nM; B = 100 nM-2 uM; C = 2-5 uM; D = 5-20 uM; E = >20uM

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound of Formula (Ia), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein:

X is absent or -L¹-X¹-L²-; L¹ is absent or —CH₂—; X¹ is selected fromthe group consisting of —O—, —S—, —SO₂—, —NR⁵—, —SO₂NR⁵—, —NR⁵SO₂—,—C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —C(═O)—,—OC(═O)NR⁵—, —NR⁵C(═O)O—, and —NR⁵C(═O)NR⁵—; each R⁵ is independentlyselected from the group consisting of H, D, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆deuteroalkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, and substituted or unsubstituted benzyl; L² is absentor substituted or unsubstituted C₁-C₄alkylene; Y is selected from thegroup consisting of H, D, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆deuteroalkyl, substituted orunsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted naphthyl, and substituted or unsubstituted heteroaryl,wherein if Y is substituted then Y is substituted with 1-4 R⁷ groups;each R⁷ is independently selected from the group consisting of D, —CN,F, Cl, Br, I, —OH, —OR⁹, —SR⁹, —S(═O)R⁹, —S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹,—S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹, —NH₂,—NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹, —OC(═O)NH₂, —OC(═O)NR⁸R⁹, —NR⁸C(═O)NH₂,—NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆deuteroalkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted C₂-C₆heterocycloalkyl, a substituted orunsubstituted aryl, or a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, asubstituted or unsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, asubstituted or unsubstituted —C₁-C₄alkylene-aryl, and a substituted orunsubstituted —C₁-C₄alkylene-heteroaryl; each R⁸ is independentlyselected from the group consisting of H, C₁-C₆alkyl, C₁-C₆fluoroalkyl,and C₁-C₆heteroalkyl; each R⁹ is independently selected from the groupconsisting of C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆heteroalkyl, asubstituted or unsubstituted C₃-C₆cycloalkyl, a substituted orunsubstituted C₂-C₆heterocycloalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted heteroaryl, a substituted orunsubstituted —C₁-C₄alkylene-C₃-C₁₀cycloalkyl, a substituted orunsubstituted —C₁-C₄alkylene-C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted —C₁-C₄alkylene-aryl, and a substituted or unsubstituted—C₁-C₄alkylene-heteroaryl; or when R⁸ and R⁹ are attached to the same Natom then R and R⁹ are taken together with the N atom to which they areattached to form a substituted or unsubstituted C₂-C₁₀heterocycle; orwhen Y and R⁵ are attached to the same N atom then Y and R⁵ are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₁₀heterocycle; provided that when ringA is pyridin4-yl then —X—Y is not —SO₂NHbenzyl,—SO₂NH(4-tert-butylphenyl) or —NHSO₂ (2,5-ditrifluoromethylphenyl). 2.The compound of claim 1, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: the groups

and —X—Y are in a 1,4-relationship on the phenyl or a 1,3-relationshipon the phenyl.
 3. The compound of claim 2, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: the groups

and —X—Y are in a 1,4-relationship on the phenyl.
 4. The compound of anyone of claims 1-3, or a pharmaceutically acceptable salt, or solvatethereof, wherein: X is absent or -L¹-X¹-L²-; L¹ is absent or —CH₂—; X¹is selected from the group consisting of —SO₂—, —NR⁵—, —SO₂NR⁵—,—NR⁵SO₂—, —C(═O)NR⁵—, —NR⁵C(═O)—, —OC(═O)—, —C(═O)O—, and —C(═O)—; eachR⁵ is independently selected from the group consisting of H, C₁-C₄alkyl,and substituted or unsubstituted benzyl; L² is absent or —CH₂—; Y isselected from the group consisting of H, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆deuteroalkyl, substitutedor unsubstituted C₁-C₆fluoroalkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted phenyl, substituted or unsubstituted benzyl, substitutedor unsubstituted naphthyl, and substituted or unsubstituted heteroaryl,wherein if Y is substituted then Y is substituted with 1-2 R⁷ groups. 5.The compound of any one of claims 1-4, wherein the compound of Formula(Ia) has the structure of Formula (Va), or a pharmaceutically acceptablesalt, or solvate thereof, wherein:


6. The compound of any one of claims 1-4, wherein the compound ofFormula (Ia) has the structure of Formula (IIa), or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:


7. The compound of any one of claims 1-4, wherein the compound ofFormula (Ia) has the structure of Formula (IIIa), or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:


8. The compound of any one of claims 1-7, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: X is absent or -L¹-X¹-L²-;L¹ is absent; X¹ is selected from the group consisting of —SO₂—, —NR⁵—,—SO₂NR⁵—, —NR⁵SO₂—, —C(═O)NR⁵—, and —NR⁵C(═O)—; each R⁵ is independentlyselected from the group consisting of H, C₁-C₄alkyl, and substituted orunsubstituted benzyl; L² is absent or —CH₂—; or when Y and R⁵ areattached to the same N atom then Y and R⁵ are taken together with the Natom to which they are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycle.
 9. The compound of any one of claims 1-8, or apharmaceutically acceptable salt, or solvate thereof, wherein: X isabsent or -L¹-X¹-L²-; L¹ is absent; X¹ is selected from the groupconsisting of —SO₂—, —NH—, —SO₂NH—, and —NHSO₂—; L² is absent or —CH₂—.10. The compound of any one of claims 1-9, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: X is absent, —SO₂—,—SO₂CH₂—, —NH—, —NHCH₂—, —SO₂NH—, —SO₂NHCH₂—, —NHSO₂— or —NHSO₂CH₂—. 11.The compound of any one of claims 1-10, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: X is absent, —SO₂—, —NH—, —SO₂NH—,—SO₂NHCH₂—, —NHSO₂— or —NHSO₂CH₂—.
 12. The compound of any one of claims1-11, or a pharmaceutically acceptable salt, or solvate thereof,wherein: X is —SO₂—.
 13. The compound of any one of claims 1-12, or apharmaceutically acceptable salt, or solvate thereof, wherein: Y isselected from the group consisting of substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl,substituted or unsubstituted phenyl, substituted or unsubstitutedbenzyl, or substituted or unsubstituted monocyclic heteroaryl, andsubstituted or unsubstituted bicyclic heteroaryl, wherein if Y issubstituted then Y is substituted with 1-2 R⁷ groups.
 14. The compoundof any one of claims 1-12, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: Y is a substituted or unsubstituted phenyl,wherein if Y is substituted then Y is substituted with 1-2 R⁷ groups.15. The compound of any one of claims 1-12, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: Y is selected from thegroup consisting of substituted or unsubstituted cyclopropyl,substituted or unsubstituted cyclobutyl, substituted or unsubstitutedcyclopentyl, and substituted or unsubstituted cyclohexyl, wherein if Yis substituted then Y is substituted with 1-2 R⁷ groups.
 16. Thecompound of any one of claims 1-12, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: Y is selected from the groupconsisting of substituted or unsubstituted cyclopentyl, and substitutedor unsubstituted cyclohexyl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.
 17. The compound of any one of claims1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted monocyclic 6-memberedheteroaryl containing 1-2 N atoms, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.
 18. The compound of any one of claims1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted monocyclic 5-memberedC₁-C₄heteroaryl containing 1-4 N atoms and 0 or 1 S or O atom, or asubstituted or unsubstituted monocyclic 5-membered C₁-C₄heteroarylcontaining 0-4 N atoms and 1 S or O atom, wherein if Y is substitutedthen Y is substituted with 1-2 R⁷ groups.
 19. The compound of any one ofclaims 1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted monocyclic heteroaryl thatis selected from the group consisting of substituted or unsubstitutedfuranyl, substituted or unsubstituted thienyl, substituted orunsubstituted pyrrolyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedimidazolyl, substituted or unsubstituted pyrazolyl, substituted orunsubstituted triazolyl, substituted or unsubstituted tetrazolyl,substituted or unsubstituted isoxazolyl, substituted or unsubstitutedisothiazolyl, substituted or unsubstituted oxadiazolyl, substituted orunsubstituted thiadiazolyl, substituted or unsubstituted pyridinyl,substituted or unsubstituted pyrimidinyl, substituted or unsubstitutedpyrazinyl, substituted or unsubstituted pyridazinyl, and substituted orunsubstituted triazinyl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.
 20. The compound of any one of claims1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted monocyclic heteroaryl thatis selected from the group consisting of substituted or unsubstitutedpyridinyl, substituted or unsubstituted pyrimidinyl, substituted orunsubstituted pyrazinyl, and substituted or unsubstituted pyridazinyl,wherein if Y is substituted then Y is substituted with 1-2 R⁷ groups.21. The compound of any one of claims 1-12, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: Y is a substituted orunsubstituted monocyclic heteroaryl that is selected from the groupconsisting of substituted or unsubstituted furanyl, substituted orunsubstituted thienyl, substituted or unsubstituted pyrrolyl,substituted or unsubstituted oxazolyl, substituted or unsubstitutedthiazolyl, substituted or unsubstituted imidazolyl, substituted orunsubstituted pyrazolyl, substituted or unsubstituted triazolyl,substituted or unsubstituted tetrazolyl, substituted or unsubstitutedisoxazolyl, substituted or unsubstituted isothiazolyl, substituted orunsubstituted oxadiazolyl, and substituted or unsubstitutedthiadiazolyl, wherein if Y is substituted then Y is substituted with 1-2R⁷ groups.
 22. The compound of any one of claims 1-12, or apharmaceutically acceptable salt, or solvate thereof, wherein: Y is asubstituted or unsubstituted C₂-C₆heterocycloalkyl that is selected fromthe group consisting of substituted or unsubstituted pyrrolidinyl,substituted or unsubstituted tetrahydrofuranyl, substituted orunsubstituted dihydrofuranyl, substituted or unsubstitutedtetrahydrothienyl, substituted or unsubstituted oxazolidinonyl,substituted or unsubstituted tetrahydropyranyl, substituted orunsubstituted dihydropyranyl, substituted or unsubstitutedtetrahydrothiopyranyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted morpholinyl, substituted or unsubstitutedthiomorpholinyl, substituted or unsubstituted thioxanyl, substituted orunsubstituted piperazinyl, substituted or unsubstituted aziridinyl,substituted or unsubstituted azetidinyl, substituted or unsubstitutedoxetanyl, substituted or unsubstituted thietanyl, substituted orunsubstituted homopiperidinyl, substituted or unsubstituted oxepanyl,substituted or unsubstituted thiepanyl, substituted or unsubstitutedoxazepinyl, substituted or unsubstituted diazepinyl, substituted orunsubstituted thiazepinyl, and substituted or unsubstituted1,2,3,6-tetrahydropyridinyl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.
 23. The compound of any one of claims1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted C₂-C₆heterocycloalkyl thatis selected from the group consisting of substituted or unsubstitutedpyrrolidinyl, substituted or unsubstituted tetrahydrofuranyl,substituted or unsubstituted oxazolidinonyl, substituted orunsubstituted tetrahydropyranyl, substituted or unsubstitutedpiperidinyl, substituted or unsubstituted morpholinyl, substituted orunsubstituted thiomorpholinyl, substituted or unsubstituted piperazinyl,substituted or unsubstituted azetidinyl, and substituted orunsubstituted oxetanyl, wherein if Y is substituted then Y issubstituted with 1-2 R⁷ groups.
 24. The compound of any one of claims1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted bicyclic heteroaryl that isselected from the group consisting of substituted or unsubstitutedindolizinyl, substituted or unsubstituted indolyl, substituted orunsubstituted benzofuranyl, substituted or unsubstitutedbenzothiophenyl, substituted or unsubstituted indazolyl, substituted orunsubstituted benzimidazolyl, substituted or unsubstituted purinyl,substituted or unsubstituted quinolizinyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted isoquinolinyl, substituted orunsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl,substituted or unsubstituted quinazolinyl, substituted or unsubstitutedquinoxalinyl, substituted or unsubstituted 1,8-naphthyridinyl, andsubstituted or unsubstituted pteridinyl wherein if Y is substituted thenY is substituted with 1-2 R⁷ groups.
 25. The compound of any one ofclaims 1-12, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y is a substituted or unsubstituted bicyclic heteroaryl that isselected from the group consisting of substituted or unsubstitutedindolizinyl, substituted or unsubstituted indolyl, substituted orunsubstituted benzofuranyl, substituted or unsubstitutedbenzothiophenyl, substituted or unsubstituted indazolyl, substituted orunsubstituted benzimidazolyl, substituted or unsubstituted purinyl,substituted or unsubstituted quinolizinyl, substituted or unsubstitutedquinolinyl, substituted or unsubstituted isoquinolinyl, substituted orunsubstituted quinazolinyl, and substituted or unsubstitutedquinoxalinyl, wherein if Y is substituted then Y is substituted with 1-2R⁷ groups.
 26. The compound of any one of claims 1-7, or apharmaceutically acceptable salt, or solvate thereof, wherein: X isabsent or -L¹-X¹-L²-; L¹ is absent or —CH₂—; X¹ is selected from thegroup consisting of —NR⁵—, —SO₂NR⁵—, and —C(═O)NR⁵—; each R⁵ isindependently selected from the group consisting of H, D, C₁-C₄alkyl,and substituted or unsubstituted benzyl; L² is absent; or Y and R⁵ aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₁₀heterocycle.
 27. The compound ofclaim 26, or a pharmaceutically acceptable salt, or solvate thereof,wherein: Y and R⁵ are taken together with the N atom to which they areattached to form a substituted or unsubstituted C₂-C₁₀heterocycle thatis a substituted or unsubstituted monocyclic C₂-C₁₀heterocycle, or asubstituted or unsubstituted bicyclic C₅-C₁₀heterocycle.
 28. Thecompound of claim 26, or a pharmaceutically acceptable salt, or solvatethereof, wherein: Y and R⁵ are taken together with the N atom to whichthey are attached to form a substituted or unsubstitutedC₂-C₁₀heterocycle that is a substituted or unsubstituted monocyclicC₂-C₁₀heterocycle, substituted or unsubstituted fused bicyclicC₅-C₁₀heterocycle, substituted or unsubstituted bridged bicyclicC₅-C₁₀heterocycle, or substituted or unsubstituted spiro bicyclicC₅-C₁₀heterocycle.
 29. The compound of claim 26, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: Y and R⁵ are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted C₂-C₁₀heterocycle that is selected from asubstituted or unsubstituted β-lactam, substituted or unsubstitutedγ-lactam, substituted or unsubstituted δ-lactam, or substituted orunsubstituted ε-lactam.
 30. The compound of claim 26, or apharmaceutically acceptable salt, or solvate thereof, wherein: Y and R⁵are taken together with the N atom to which they are attached to formsubstituted or unsubstituted aziridinyl, substituted or unsubstitutedazetidinyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted piperidinyl, substituted or unsubstituted morpholinyl,substituted or unsubstituted thiomorpholinyl, substituted orunsubstituted piperazinyl, substituted or unsubstituted azepanyl,substituted or unsubstituted indolinyl, substituted or unsubstitutedisoindolinyl, substituted or unsubstituted tetrahydroquinolinyl,substituted or unsubstituted tetrahydroisoquinolinyl, or substituted orunsubstituted 8-oxa-3-azabicyclo[3.2.1]oct-3-yl.
 31. The compound of anyone of claims 1-30, or a pharmaceutically acceptable salt, or solvatethereof, wherein: each R⁷ is independently selected from the groupconsisting of D, —CN, F, Cl, Br, I, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,—S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹, —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹, —NH₂, —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹,—OC(═O)NH₂, —OC(═O)NR⁸R⁹, —NRC(═O)NH₂, —NR⁸C(═O)NR⁸R⁹, —NR⁸C(═O)R⁹,—NR⁸C(═O)OR⁹, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted C₂-C₆heterocycloalkyl, a substituted orunsubstituted phenyl, or a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —CH₂—C₃-C₆cycloalkyl, a substituted orunsubstituted —CH₂—C₂-C₆heterocycloalkyl, a substituted or unsubstituted—CH₂-phenyl, and a substituted or unsubstituted —CH₂-heteroaryl; each R⁸is independently selected from the group consisting of H, C₁-C₆alkyl,C₁-C₆fluoroalkyl, and C₁-C₆heteroalkyl; each R⁹ is independentlyselected from the group consisting of C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted C₂-C₆heterocycloalkyl, a substituted orunsubstituted phenyl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted —CH₂—C₃-C₁₀cycloalkyl, a substituted orunsubstituted —CH₂—C₂-C₁₀heterocycloalkyl, a substituted orunsubstituted —CH₂-phenyl, and a substituted or unsubstituted —CH₂—heteroaryl; or when R⁸ and R⁹ are attached to the same N atom then R⁸and R⁹ are taken together with the N atom to which they are attached toform a substituted or unsubstituted C₂-C₁₀heterocycle;
 32. The compoundof any one of claims 1-30, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: each R⁷ is independently selected from thegroup consisting of D, —CN, F, Cl, Br, —OH, —OR⁹, —SR⁹, —S(═O)R⁹,—S(═O)₂R⁹, —N(R⁸)S(═O)₂R⁹, —S(═O)₂NH₂, —S(═O)₂NR⁸R⁹, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R⁸, —OCO₂R⁹, —NH₂, —NR⁸R⁹, —C(═O)NH₂, —C(═O)NR⁸R⁹,—NR⁸C(═O)R⁹, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆fluoroalkyl,C₁-C₆heteroalkyl, a substituted or unsubstituted C₃-C₆cycloalkyl, asubstituted or unsubstituted monocyclic C₂-C₆heterocycloalkyl, asubstituted or unsubstituted phenyl, or a substituted or unsubstitutedmonocyclic heteroaryl, a substituted or unsubstituted—CH₂—C₃-C₆cycloalkyl, a substituted or unsubstituted —CH₂-monocyclicC₂-C₆heterocycloalkyl, and a substituted or unsubstituted—CH₂-monocyclic heteroaryl;
 33. The compound of any one of claims 1-30,or a pharmaceutically acceptable salt, or solvate thereof, wherein: eachR⁷ is independently selected from the group consisting of —CN, F, Cl,Br, —OH, —OCH₃, —OCH₂CH₃, —OCF₃, —S(═O)₂CH₃, —NHS(═O)₂CH₃, —S(═O)₂NH₂,—C(═O)CH₃, —C(═O)CH₂CH₃, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, —NH₂, —NHCH₃,—N(CH₃)₂, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃),—C(CH₃)₃, —CH₂F, —CHF₂, —CF₃, substituted or unsubstituted phenyl,substituted or unsubstituted cyclopentyl, substituted or unsubstitutedcyclohexyl, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted tetrahydrofuranyl, substituted or unsubstitutedoxazolidinonyl, substituted or unsubstituted tetrahydropyranyl,substituted or unsubstituted piperidinyl, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted thiomorpholinyl, substitutedor unsubstituted piperazinyl, substituted or unsubstituted azetidinyl,substituted or unsubstituted oxetanyl, substituted or unsubstitutedfuranyl, substituted or unsubstituted thienyl, substituted orunsubstituted pyrrolyl, substituted or unsubstituted oxazolyl,substituted or unsubstituted thiazolyl, substituted or unsubstitutedimidazolyl, substituted or unsubstituted pyrazolyl, substituted orunsubstituted triazolyl, substituted or unsubstituted tetrazolyl,substituted or unsubstituted isoxazolyl, substituted or unsubstitutedisothiazolyl, substituted or unsubstituted oxadiazolyl, substituted orunsubstituted thiadiazolyl, substituted or unsubstituted pyridinyl,substituted or unsubstituted pyrimidinyl, substituted or unsubstitutedpyrazinyl, substituted or unsubstituted pyridazinyl, and substituted orunsubstituted —CH₂-phenyl.
 34. A compound that is:1-(4-Fluorophenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-Chlorophenyl)-3-(pyridin-4-ylmethyl)urea;1-(Pyridin-4-ylmethyl)-3-(p-tolyl)urea; Ethyl2-(3-(pyridin-4-ylmethyl)ureido)benzoate; Ethyl3-(3-(pyridin-4-ylmethyl)ureido)benzoate;1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)urea;1-(Pyridin-4-ylmethyl)-3-(4-(trifluoromethoxy)phenyl)urea;1-(4-Methoxyphenyl)-3-(pyridin-4-ylmethyl)urea;N,N-diethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide;N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(p-tolyl)benzamide;N-phenyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-ethyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-methyl-N-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-hydroxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-butyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-cyclopentyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide; Ethyl4-(3-(pyridin-4-ylmethyl)ureido)benzoate;4-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid;3-(3-(Pyridin-4-ylmethyl)ureido)benzoic acid;4-(3-(Pyridin-4-ylmethyl)ureido)benzamide;N-propyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-Isopropyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N,N-dimethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-morpholinoethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-cyclohexyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-(piperidin-1-yl)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;N-isobutyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-cyclobutyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(cyclopropylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(pyridin-4-ylmethyl)ureido)-N-(tetrahydrofuran-3-yl)benzamide;N-(2-methoxyethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-phenethyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;1-(4-(Morpholine-4-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-(4-Methylpiperazine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-(Piperidine-1-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(Pyridin-4-ylmethyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)urea;N-(cyclopentylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;1-(4-(8-Oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;N-(pyridin-4-ylmethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-methylphenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-fluorophenethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-ethoxypropyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-(dimethylamino)ethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;1-(4-(Isoindoline-2-carbonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(Pyridin-4-ylmethyl)-3-(4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)urea;N-(4-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-chlorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-fluorophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(o-tolyl)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(m-tolyl)benzamide;N-(4-(methoxymethyl)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-methoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-(dimethylamino)phenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(2-(trifluoromethoxy)phenyl)benzamide;4-(3-(pyridin-4-ylmethyl)ureido)-N-(3-(trifluoromethoxy)phenyl)benzamide;4-(3-(pyridin-4-ylmethyl)ureido)-N-(4-(trifluoromethoxy)phenyl)benzamide;N-(4-ethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-isopropoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide; Methyl4-(4-(3-(pyridin-4-ylmethyl)ureido)benzamido)benzoate;N-(4-cyanophenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3,4-dimethylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(3,4-dimethoxyphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(benzo[d][1,3]dioxol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(4-methoxy-3-methylphenyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(pyridin-2-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;N-(pyridin-3-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(pyridin-4-ylmethyl)ureido)-N-(pyrimidin-5-yl)benzamide;N-(3-methylisoxazol-5-yl)-4-(3-(pyridin-4-ylmethyl)ureido)benzamide;4-(3-(Pyridin-4-ylmethyl)ureido)-N-(thiophen-2-yl)benzamide;N-Cyclohexyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-cyclopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrrolidin-3-yl-benzenesulfonamide;N-(1-Methyl-pyrrolidin-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(tert-butyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-Dimethylamino-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclopropylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclobutylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-pyrrolidin-1-yl-ethyl)-benzensulfonamide;N-[2-(4-Methyl-piperazin-1-yl)-ethyl]-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Morpholin-4-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Piperidin-1-yl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Hydroxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(tetrahydro-furan-3-yl)-benzenesulfonamide;N-(2-Methoxy-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Methoxy-propyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(1-Ethyl-pyrrolidin-2-ylmethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-neopentyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(1-Cyclobutyl-ethyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(3-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(4-fluorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Chloro-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-chlorobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(3-Methoxy-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-methoxybenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-methylbenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Cyano-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-cyanobenzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;2-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester;3-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester;4-{[4-(3-Pyridin-4-ylmethyl-ureido)-benzenesulfonylamino]-methyl}-benzoicacid methyl ester;4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethyl-benzyl)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(3-trifluoromethoxy-benzyl)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(4-trifluoromethoxy-benzyl)-benzenesulfonamide;N-(2-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-Dimethylamino-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-Methanesulfonyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N,N-dimethyl-4-((4-(3-(pyridin-4-ylmethyl)ureido)phenylsulfonamido)methyl)benzenesulfonamide;N-(4-((dimethylamino)methyl)benzyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(4-Methoxymethyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(1-phenylethyl)-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-Pyridin-4-ylmethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-benzenesulfonamide;N,N-Dimethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N,N-Diethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Hydroxy-ethyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclopentyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-benzyl-N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-(2-Fluoro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Chloro-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;1-[4-(Piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;N-Cyclobutylmethyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclohexyl-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclopentyl-N-isobutyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Cyclopentyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-methyl-4-(3-(pyridin-4-ylmethyl)ureido)-N-(2-(trifluoromethyl)benzyl)benzenesulfonamide;N-Methyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2-trifluoromethoxy-benzyl)-benzenesulfonamide;N-(2-Methoxy-benzyl)-N-methyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-N-isopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-N-ethyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-N-cyclopropyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-N-propyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N,N-Dibenzyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Methyl-N-(2-methyl-benzyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Benzyl-4-(3-pyridin-4-ylmethyl-ureido)-N-(2,2,2-trifluoro-ethyl)-benzenesulfonamide;N-Benzyl-N-phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;Pyridin-4-ylmethyl-3-[4-(pyrrolidine-1-sulfonyl)-phenyl]-urea;1-[4-(Piperidine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(Morpholine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1,3-Dihydro-isoindole-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(8-Chloro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;Pyridin-4-ylmethyl-3-[4-(8-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-urea;Pyridin-4-ylmethyl-3-[4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-urea;1-[4-(8-Fluoro-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(8-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3-Methyl-3,4-dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;N-Phenyl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(2-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(3-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(4-Methoxy-phenyl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-o-tolyl-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-m-tolyl-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-p-tolyl-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-thiazol-2-yl-benzenesulfonamide;N-(4,5-Dimethyl-oxazol-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-(5-Methyl-isoxazol-3-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;4-(3-Pyridin-4-ylmethyl-ureido)-N-pyrimidin-2-yl-benzenesulfonamide;N-(4-Methyl-pyrimidin-2-yl)-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-Pyridin-2-yl-4-(3-pyridin-4-ylmethyl-ureido)-benzenesulfonamide;N-cyclopentyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-benzyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;1-(3-(morpholinosulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;N-(cyclobutylmethyl)-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;N-phenethyl-3-(3-(pyridin-4-ylmethyl)ureido)benzenesulfonamide;4-(3-pyridin-4-ylmethyl-ureido)-N-(2-chloro-phenyl)-benzenesulfonamide;4-(3-pyridin-4-ylmethyl-ureido)-N-(3-chloro-phenyl)-benzenesulfonamide;4-(3-pyridin-4-ylmethyl-ureido)-N-(4-chloro-phenyl)-benzenesulfonamide;1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-Benzenesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea;1-(4-Phenylmethanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea;1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;N-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;2-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;3-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;4-Methoxy-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;2-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;3-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;4-Chloro-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;N-[4-(3-Benzyl-ureido)-phenyl]-C-phenyl-methanesulfonamide;1-(2-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide;1-(3-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide;1-(4-chlorophenyl)-N-(4-(3-(pyridin-4-ylmethyl)ureido)phenyl)methanesulfonamide;N-Methyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;N-Isopropyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;N-Methyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-benzenesulfonamide;N-Isopropyl-C-phenyl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;N-Phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;N-Methyl-N-phenyl-C-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-(4-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-(4-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-(4-Cyclopropyl-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-Biphenyl-4-yl-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-(4-Cyano-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;1-[4-(3-Bromo-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-urea;C-(2-Bromo-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;C-(3-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;N-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-m-tolyl-methanesulfonamide;C-(3-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;N-[4-(3-Pyridin-4-ylmethyl-ureido)-phenyl]-C-p-tolyl-methanesulfonamide;C-(2-Methoxy-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;1-[4-(4-Fluoro-phenylmethanesulfonyl)-phenyl]-3-(1H-pyrazol-4-yl)-urea;1-[4-(2-Methyl-benzylsulfanylamino)-phenyl]-3-pyridin-4-ylmethyl-urea;C-(2-Fluoro-phenyl)-N-[4-(3-pyridin-4-ylmethyl-ureido)-phenyl]-methanesulfonamide;1-Pyridin-4-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-Pyridin-4-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea;1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(Pyridin-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(Pyridin-4-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea;1-Pyridin-4-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea;1-Pyridin-4-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea;1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea;1-(Pyridin-4-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-(4-Cyclohexanesulfonyl-phenyl)-3-pyridin-4-ylmethyl-urea;1-Pyridin-4-ylmethyl-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;Pyridin-4-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea;1-Pyridin-4-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;of1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-Pyridin-4-ylmethyl)-3-(4-(thiazol-5-ylsulfonyl)phenyl)urea;1-[4-(Pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-Pyridin-4-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea;1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-((4-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(Benzothiazol-2-ylamino)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-Benzothiazol-4-yl-phenyl)-3-pyridin-4-ylmethyl-urea;1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((5-Phenylthiazol-2-yl)amino)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(1H-Indazol-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-(1,4-Dimethyl-1H-indazol-3-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2-Pyridin-3-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2-Pyridin-4-yl-benzenesulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-pyridin-4-ylmethyl-urea;1-(4-((2′-Chloro-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((4′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((2-(6-Methoxypyridin-3-yl)phenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((3′-Cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-((2′-Methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(3-Cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(4-(5-phenylthiazol-2-yl)phenyl)-3-(pyridin-4-ylmethyl)urea;1-(2-Cyano-4-((3,5-difluorophenyl)sulfonyl)phenyl)-3-(pyridin-4-ylmethyl)urea;or a pharmaceutically acceptable salt, or solvate thereof.
 35. Acompound that is: Ethyl 4-(3-((1H-pyrazol-4-yl)methyl)ureido)benzoate;N-(3-Chloro-phenyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzamide;4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-methoxyphenyl)benzamide;14-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(2-chlorophenyl)benzamide;4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-methoxyphenyl)benzamide;4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(4-chlorophenyl)benzamide;4-(3-((1H-pyrazol-4-yl)methyl)ureido)-N-(3-methoxyphenyl)benzamide;4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-N-pyridin-2-yl-benzenesulfonamide;N-Benzyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(8-Oxa-3-aza-bicyclo[3.2.1]octane-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;N-Cyclobutylmethyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-Phenyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-Cyclopentyl-N-methyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-Benzyl-N-isopropyl-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-(3-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-(2-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-(2-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-(4-Methoxy-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;N-(4-Chloro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;1-[4-(3-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(4-Chloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(2-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(4-Benzenesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;N-{4-[3-(1H-Pyrazol-4-ylmethyl)-ureido]-phenyl}-benzenesulfonamide;N-(4-(3-((1H-pyrazol-4-yl)methyl)ureido)phenyl)-1-phenylmethanesulfonamide;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-2-ylsulfonyl)phenyl)urea;1-[4-(5-Methyl-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-fluorophenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-fluorophenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-fluorophenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-4-sulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-3-sulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(toluene-2-sulfonyl)-phenyl]-urea;1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;C-(3-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide;C-(2-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide;C-(4-Chloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide;1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea;C-(3,4-Dichloro-phenyl)-N-{4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-phenyl}-methanesulfonamide;N-(3-Fluoro-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(pyrimidin-5-ylsulfonyl)phenyl)urea;1-(4-Cyclohexanesulfonyl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea;1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;N-(4-Methyl-benzyl)-4-[3-(1H-pyrazol-4-ylmethyl)-ureido]-benzenesulfonamide;1-[4-(2,4-Dichloro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea;1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;of1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(Pyrazine-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(1-Isopropyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(1-Isobutyl-piperidine-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;of1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-yl)phenyl)urea;1-[4-(1H-Indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-benzylthiazol-2-yl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(benzo[d]thiazol-2-ylamino)phenyl)urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-o-tolyl-thiazol-2-ylamino)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-m-tolyl-thiazol-2-ylamino)-phenyl]-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(4-p-tolyl-thiazol-2-ylamino)-phenyl]-urea;1-{4-[4-(2-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,5-dimethyl-1H-indazol-3-yl)phenyl)urea;1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-{4-[4-(3-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-{4-[4-(4-Fluoro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(2-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(3-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea;1-(4-Benzothiazol-4-yl-phenyl)-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,7-dimethyl-1H-indazol-3-yl)phenyl)urea;1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-{4-[4-(2-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-{4-[4-(3-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-{4-[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-phenyl}-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4-(4-methoxyphenyl)thiazol-2-yl)amino)phenyl)urea;1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-3-ylsulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-([1,1′-biphenyl]-2-ylsulfonyl)phenyl)urea;1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-chloro-1-methyl-1H-indazol-3-yl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-(1,4-dimethyl-1H-indazol-3-yl)phenyl)urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-3-yl-benzenesulfonyl)-phenyl]-urea;1-[4-(3-Iodo-benzenesulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(2′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(3′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(4′-Fluoro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(2′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(3′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-(1H-Pyrazol-4-ylmethyl)-3-[4-(2-pyridin-4-yl-benzenesulfonyl)-phenyl]-urea;1-[4-(3′-Chloro-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(4′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(3′-Methyl-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-[4-(4′-Methoxy-biphenyl-2-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-chloro-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((4′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2-(6-methoxypyridin-3-yl)phenyl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((3′-cyano-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea;1-((1H-Pyrazol-4-yl)methyl)-3-(4-((2′-methyl-[1,1′-biphenyl]-2-yl)sulfonyl)phenyl)urea;1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-(1H-pyrazol-4-ylmethyl)-urea;or a pharmaceutically acceptable salt, or solvate thereof.
 36. Acompound that is: Ethyl 4-(3-(oxazol-5-ylmethyl)ureido)benzoate;N-Benzyl-N-isopropyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamide;1-[4-(3,4-Dihydro-1H-isoquinoline-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;N-Benzyl-4-(3-oxazol-5-ylmethyl-ureido)-benzenesulfonamide;1-(4-Benzenesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea;N-[4-(3-Oxazol-5-ylmethyl-ureido)-phenyl]-benzenesulfonamide;N-Oxazol-5-ylmethyl-2-(4-phenylmethanesulfonylamino-cyclohexa-1,5-dienyl)-acetamide;1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(4-Cyano-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(3-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide;1-(4-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide;1-(3,4-Dichlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide;1-(2-Chlorophenyl)-N-(4-(3-(oxazol-5-ylmethyl)ureido)phenyl)methanesulfonamide;1-Oxazol-5-ylmethyl-3-[4-(toluene-4-sulfonyl)-phenyl]-urea;1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-2-ylsulfonyl)phenyl)urea;1-(4-((3-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(Oxazol-5-ylmethyl)-3-(4-(pyridin-4-ylsulfonyl)phenyl)urea;1-(4-((2-Methoxyphenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-Oxazol-5-ylmethyl-3-[4-(toluene-3-sulfonyl)-phenyl]-urea;1-Oxazol-5-ylmethyl-3-[4-(toluene-2-sulfonyl)-phenyl]-urea;1-[4-(5-Chloro-pyridine-2-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-((2-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-((3-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-((4-Fluorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-[4-(2-Chloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(2-trifluoromethyl-benzenesulfonyl)-phenyl]-urea;1-(Oxazol-5-ylmethyl)-3-(4-((3-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-(Oxazol-5-ylmethyl)-3-(4-((4-(trifluoromethyl)phenyl)sulfonyl)phenyl)urea;1-(4-Cyclohexanesulfonyl-phenyl)-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(6-Methyl-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-((4-Chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea;1-[4-(1-Methyl-piperidine-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(3-trifluoromethoxy-benzenesulfonyl)-phenyl]-urea;1-[4-(3-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(3,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(thiazole-2-sulfonyl)-phenyl]-urea;1-[4-(3,4-Dichloro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(pyridine-3-sulfonyl)-phenyl]-urea;1-[4-(3,5-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(1-Isopropyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(pyrazine-2-sulfonyl)-phenyl]-urea;1-[4-(2,4-Difluoro-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(6-Methoxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(4-Methoxy-benzenesulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(1-Methyl-1H-pyrazole-4-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-Oxazol-5-ylmethyl-3-[4-(pyrimidine-2-sulfonyl)-phenyl]-urea;1-Oxazol-5-ylmethyl-3-{4-[1-(tetrahydro-pyran-4-yl)-piperidine-4-sulfonyl]-phenyl}-urea;1-[4-(1H-Indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-(Benzo[d]thiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-[4-(6-Hydroxy-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(6-Chloro-pyridine-3-sulfonyl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(1-Methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(Oxazol-5-ylmethyl)-3-(4-((4-phenylthiazol-2-yl)amino)phenyl)urea;1-(4-(5-Benzylthiazol-2-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-((1H-pyrazol-4-yl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-(Benzo[d]thiazol-2-ylamino)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-(1,5-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-[4-(1,6-Dimethyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-Benzothiazol-4-yl-phenyl)-3-oxazol-5-ylmethyl-urea;1-[4-(5-Methoxy-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(5-Fluoro-1-methyl-1H-indazol-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-[4-(1H-Benzoimidazol-4-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-([1,1′-Biphenyl]-3-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(4-([1,1′-Biphenyl]-2-ylsulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-[4-(1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-(5-Chloro-1-methyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-(Oxazol-5-ylmethyl)-3-(4-((5-phenylthiazol-2-yl)amino)phenyl)urea;1-(Oxazol-5-ylmethyl)-3-(4-(5-phenylthiazol-2-yl)phenyl)urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;1-(4-(1,7-Dimethyl-1H-indazol-3-yl)phenyl)-3-(oxazol-5-ylmethyl)urea;1-[4-(1-Methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-phenyl]-3-oxazol-5-ylmethyl-urea;or a pharmaceutically acceptable salt, or solvate thereof.
 37. Apharmaceutical composition comprising a compound of any one of claims1-36, or a pharmaceutically acceptable salt, or solvate thereof, and atleast one pharmaceutically acceptable excipient.
 38. The pharmaceuticalcomposition of claim 37, wherein the pharmaceutical composition isformulated for oral administration, intravenous injection, subcutaneousinjection, inhalation, nasal administration, topical administration,ophthalmic administration or otic administration.
 39. The pharmaceuticalcomposition of claim 37, wherein the pharmaceutical composition is atablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a colloid, a dispersion, asuspension, a solution, an emulsion, an ointment, a lotion, an eye dropor an ear drop.
 40. The pharmaceutical composition of claim 37, furthercomprising another therapeutic agent.
 41. A method of treating a diseaseor condition mediated by nicotinamide phosphoribosyltransferase (NAMPT)activity in a mammal comprising administering a compound of any one ofclaims 1-36, or a pharmaceutically acceptable salt, or solvate thereof,to the mammal.
 42. The method of claim 41, wherein the disease orcondition is cancer.
 43. The method of claim 41, wherein the disease orcondition is hyperproliferative disease or condition.
 44. The method ofclaim 41, wherein the disease or condition is an inflammatory disease orcondition.
 45. The method of claim 41, wherein the disease or conditionis a metabolic disorder.
 46. The method of claim 41, wherein the diseaseor condition is a neurodegenerative disorder.
 47. The method of claim41, wherein the disease or condition is a muscle wasting disorder. 48.The method of claim 41, wherein the disease or condition is aneurodegenerative disease.
 49. Use of a compound of any one of claims1-36, or a pharmaceutically acceptable salt, or solvate thereof, in themanufacture of a medicament for the treatment or prevention of a diseaseor condition that is mediated by NAMPT activity.